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A Review of Immune Checkpoint Blockade for the General Surgeon

Published:October 10, 2022DOI:https://doi.org/10.1016/j.jss.2022.08.040

      Abstract

      The immune system is a complex and interconnected system that has evolved to protect its host from foreign pathogens. CD8+ T cells are a type of immune cell that can be directly lethal to tumor cells. However, their tumor killing capabilities can be inhibited by checkpoint molecules. During the last decade, the development of medications that block these checkpoint molecules has revolutionized treatment for some cancer types and indications for use continue to grow. As usage of immunotherapy increases, toxicities and adverse events unique to immunotherapy are becoming more prevalent. Here, we review the commonly targeted inhibitory molecules along with their food and drug administration-approved indications in various cancer therapeutic regimens, immunotherapy-related toxicities, and how this may impact surgical planning.

      Keywords

      Introduction

      The immune system is a complex and interconnected system that has evolved to protect its host from foreign pathogens. The immune system has two major components: innate immunity and adaptive immunity. The innate immune system which comprises neutrophils, macrophages, natural killer cells, and the complement system, acts immediately upon recognizing a foreign antigen to tag and phagocytose or lyse its targets. The late or adaptive immune system which comprises B cells and T cells and is marked by its specificity as well as its ability to form memory cells which can recognize antigens upon repeated exposures. This response is dependent upon B and T cells recognizing antigen, which are peptides derived from foreign pathogens (or in the case of autoimmunity, the self). B cells have the capacity to produce pathogen- or tumor-specific antibodies after activation, which can then tag unwanted cells for clearance through antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis, or the complement system. In contrast, T cells use effector functions to kill pathogens directly. Together, the innate and adaptive immune systems work in a coordinated effort to help the host remain disease-free.
      • Abbas A.K.
      • Lichtman A.H.
      • Pillai S.
      Cellular and Molecular Immunology.
      • Delves P.J.
      • Roitt I.M.
      The immune system. Second of two parts.
      • Hillion S.
      • Arleevskaya M.I.
      • Blanco P.
      • et al.
      The innate part of the adaptive immune system.
      The immune system is not only designed to kill foreign pathogens but also plays a critical role in the surveillance, detection, and elimination of cancer cells.
      • Raskov H.
      • Orhan A.
      • Christensen J.P.
      • Gogenur I.
      Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy.
      CD8+ T cells, also known as cytotoxic T lymphocytes, are capable of killing tumor cells and their presence in the tumor microenvironment is associated with improved prognosis in cancer.
      • Oshi M.
      • Asaoka M.
      • Tokumaru Y.
      • et al.
      CD8 T cell score as a prognostic biomarker for triple negative breast cancer.
      ,
      • Blessin N.C.
      • Li W.
      • Mandelkow T.
      • et al.
      Prognostic role of proliferating CD8(+) cytotoxic Tcells in human cancers.
      In order to be effective at tumor cell killing, CD8+ T cells require two important signals. First, they must recognize antigens presented by major histocompatibility complexes.
      • Zhang N.
      • Bevan M.J.
      CD8(+) T cells: foot soldiers of the immune system.
      The second signal can either stimulate or suppress T cell activation. Therefore, this second signal molecule serves as either a co-stimulatory signal or a “checkpoint” for CD8+ T cell effector functions. Tumor cells can display inhibitory checkpoint molecules which suppress CD8+ T cells responses and allow the tumor to evade the immune system.
      • Vinay D.S.
      • Ryan E.P.
      • Pawelec G.
      • et al.
      Immune evasion in cancer: mechanistic basis and therapeutic strategies.
      In the last decade, drugs which block this second inhibitory signal, called immune checkpoint blockade, release the brakes that these inhibitory molecules have placed on CD8+ T cells. This then unleashes the power of CD8+ T cells to kill tumor cells.
      The purpose of this review is to summarize our current understanding of immune checkpoint blockade (ICB). We will define checkpoint molecules and their associated drugs. We will also describe the indications for checkpoint blockade in the non-metastatic setting. Lastly, we will detail the potential complications of ICB and their implications for surgeons.

      Checkpoint molecules

      As mentioned above, CD8+ T cells can either be activated or suppressed by a second signal after they engage with a major histocompatibility complex-bound antigen. The balance created by the second signal is important to preserve self-tolerance and prevent autoimmunity while still promoting host defense. Costimulatory and coinhibitory ligands and their receptors are present on T cells as well as the antigen-presenting cells that present foreign antigens. The main costimulatory molecules for T cells are CD28, OX40, GITR, and 4-1BB.
      • Azuma M.
      Co-Signal molecules in T-cell activation : historical overview and perspective.
      Coinhibitory molecules are often upregulated on T cells through a negative feedback loop. These molecules are also present on immune cells that regulate T cell activity, antigen-presenting cells, and normal nucleated cells to prevent autoimmunity. We discuss four different immune checkpoint molecules along with the names of the corresponding Food and Drug Administration (FDA)–approved monoclonal antibody therapies (Fig., Table 1).
      Figure thumbnail gr1
      Fig.Checkpoint inhibitory and stimulatory molecules. Immune checkpoint receptors and their ligands. Immune checkpoint molecules bound to their respective ligands produce a positive or negative signal to CD8+ T cells. MHC: major histocompatibility complex Figure created with Biorender.com.
      Table 1List of FDA–approved checkpoint blockade drugs.
      TargetAgent
      CTLA-4Ipilimumab
      PD-1Pembrolizumab
      Nivolumab
      Cemiplimab
      Dostarlimab
      PD-L1/L2Atezolizumab
      Avelumab
      Durvalumab
      LAG-3Relatlimab

      Cytotoxic T lymphocyte antigen-4

      Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an intracellular protein which is a potent inhibitor of T cell responses that translocates to the cell surface after T cell activation. It is homologous to the costimulatory molecule CD28 and binds to the same ligand (CD80) with a higher affinity. By outcompeting CD28, it prevents proliferation and activation of T cells. In the setting of cancer, CTLA-4 is often found on regulatory T cells that inhibit CD8+ T cells. Ipilimumab is the only ICB approved by the FDA in 2011 that targets CTLA-4.
      • Ribas A.
      • Wolchok J.D.
      Cancer immunotherapy using checkpoint blockade.

      Programmed death-1

      Programmed death-1 (PD-1) is a transmembrane protein that is upregulated with repetitive stimulation of T cells. PD-1 has two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), that when engaged, inhibit T cells. Tumor cells upregulate PD-L1 and PD-L2 to diminish immune cell killing. In addition to inhibition of intracellular T cell signaling, PD-1 engagement depresses CD8+ T cell metabolism and decreases transcription of prosurvival factors.
      • Kalia V.
      • Yuzefpolskiy Y.
      • Vegaraju A.
      • et al.
      Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice.
      Nivolumab and pembrolizumab are checkpoint blockers that target the PD-1 molecule and were both FDA approved in 2014. In 2018 and 2021, cemiplimab and dostarlimab were also approved, respectively.
      • Baumeister S.H.
      • Freeman G.J.
      • Dranoff G.
      • Sharpe A.H.
      Coinhibitory pathways in immunotherapy for cancer.
      ,
      • Yi M.
      • Zhu S.
      • Ge K.
      • Wu K.
      Combination strategies with PD-1/PD-L1 blockade: current advances and future directions.

      Programmed death-ligand 1/2

      PD-L1/L2 are cell surface proteins that are expressed on tumor cells and even some immune cells in the tumor microenvironment. Its receptor is PD-1 and blockade of PD-L1/L2 results in enhanced antitumor immunity, similar to PD-1 blockade. Expression of PD-L1/L2 in the tumor microenvironment is upregulated by interferon-γ, which is an effector molecule of CD8+ T cells. Atezolizumab, avelumab, and durvalumab are all FDA–approved PD-L1 inhibitors.
      • Baumeister S.H.
      • Freeman G.J.
      • Dranoff G.
      • Sharpe A.H.
      Coinhibitory pathways in immunotherapy for cancer.
      ,
      • Wu Q.
      • Jiang L.
      • Li S.C.
      • He Q.J.
      • Yang B.
      • Cao J.
      Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway.

      Lymphocyte activation gene-3

      Lymphocyte activation gene-3 (LAG-3) is a transmembrane receptor expressed on CD8+ T cells and is further upregulated by T cell activation. Its exact ligand is unknown. Upon engagement, LAG-3 negatively regulates CD4+ and CD8+ T cell activation, proliferation, and function. Relatlimab is the only FDA–approved LAG-3 inhibitor.
      • Maruhashi T.
      • Sugiura D.
      • Okazaki I.M.
      • Okazaki T.
      LAG-3: from molecular functions to clinical applications.

      FDA-Approved Indications for Immune Checkpoint Blockade in Nonmetastatic Cancer

      Advanced disease

      Mismatch repair/Microsatellite instability

      Mismatched nucleotides in DNA occur as a result of chemical and physical insults as well as polymerase integration errors.
      • Fishel R.
      Mismatch repair.
      Mismatch repair (MMR) is one of the DNA repair pathways that recognizes and replaces these mismatched nucleotides. Loss of function in MMR genes, such as MLH-1, MSH-2, MSH-6, and PMS-2 leads to MMR deficiency associated with microsatellite instability (MSI). The MSI is associated with an increased risk of numerous cancers given the correlative increase in mutations, which is particularly well-studied in colorectal cancers.
      • Sahin I.H.
      • Akce M.
      • Alese O.
      • et al.
      Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms.
      MMR/MSI and the resultant tumor mutational burden creates a tumor microenvironment which is highly infiltrated with immune cells that facilitates the checkpoint blockade efficacy. ICB has been approved for dMMR (MMR deficient) or MSI-H (MSI-high) solid cancers including colorectal,
      • André T.
      • Shiu K.K.
      • Kim T.W.
      • et al.
      Pembrolizumab in microsatellite-instability-high advanced colorectal cancer.
      pancreatic, endometrial,
      • Pirs B.
      • Skof E.
      • Smrkolj V.
      • Smrkolj S.
      Overview of immune checkpoint inhibitors in gynecological cancer treatment.
      and prostate cancer.
      • Hansen A.R.
      • Massard C.
      • Ott P.A.
      • et al.
      Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.
      Most recently, dMMR/MSI-H was FDA approved as a pan-cancer biomarker for pembrolizumab use given the tissue-agnostic association between dMMR and response to checkpoint blockade.
      • Le D.T.
      • Uram J.N.
      • Wang H.
      • et al.
      PD-1 blockade in tumors with mismatch-repair deficiency.
      Lynch syndrome, or hereditary nonpolyposis colorectal cancer, is a hereditary syndrome marked by pathogenic mutations in one of the four MMR genes and is the most common hereditary colon cancer syndrome. It is also associated with endometrial cancer, ovarian cancer, urothelial cancer, small bowel cancer, gastric cancer, and brain tumors. In a study looking at 27 tumor types, 3.8% were MSI-H.
      • Bonneville R.
      • Krook M.A.
      • Kautto E.A.
      • et al.
      Landscape of microsatellite instability across 39 cancer types.
      About 14% of all colon cancers are MSI-H, and the majority occur as a result of sporadic inactivation of the MMR pathway. About 2%-3% of all colorectal and endometrial cancer causes are associated with germline mutations in an MMR gene and cancer-specific inactivation of the second allele. Interestingly, in patients with dMMR/MSI-H colorectal or noncolorectal cancer associated with Lynch syndrome, response rates to ICB appear to be similar to those with sporadic dMMR/MSI-H cancers.
      • Roudko V.
      • Cimen Bozkus C.
      • Greenbaum B.
      • Lucas A.
      • Samstein R.
      • Bhardwaj V.
      Lynch syndrome and MSI-H cancers: from mechanisms to “Off-The-Shelf” cancer vaccines.
      ,
      • Therkildsen C.
      • Jensen L.H.
      • Rasmussen M.
      • Bernstein I.
      An update on immune checkpoint therapy for the treatment of Lynch syndrome.
      Most recently, a clinical trial of single-agent anti-PD-1 monoclonal antibody (dostarlimab) was given neoadjuvantly to stage II or III patients with dMMR colorectal cancer, and 100% of the 12 patients enrolled had a complete clinical response, and none had required surgery or chemoradiotherapy at follow-up.
      • Cercek A.
      • Lumish M.
      • Sinopoli J.
      • et al.
      PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer.
      Each of the initial 14 patients enrolled had confirmed MSI and high tumor mutational burden. While none had a family history of Lynch syndrome, 57% were found to have pathogenic mutations in genes associated with Lynch syndrome.

      Skin cancer

      Melanoma

      In 2011, ipilimumab was the first ICB to receive approval for advanced or metastatic melanoma patients.
      • Huang A.C.
      • Zappasodi R.
      A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance.
      The approval of ipilimumab, based on the MDX010-20 trial, led to the approval of several other ICB drugs for use in patients with unresectable or stage III melanoma.
      • Hodi F.S.
      • O’Day S.J.
      • McDermott D.F.
      • et al.
      Improved survival with ipilimumab in patients with metastatic melanoma.
      For example, in 2014, anti-PD-1 inhibitors, nivolumab or pembrolizumab alone, were found to extend survival.
      • Huang A.C.
      • Zappasodi R.
      A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance.
      Further studies have shown that combination therapy of nivolumab and ipilimumab improved progression free and overall survival compared to monotherapy with either agent.
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • et al.
      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
      Combination of relatlimab (LAG-3 blocking antibody) and nivolumab are also approved for use based on the combination’s improved outcomes compared to nivolumab alone.
      • Tawbi H.A.
      • Schadendorf D.
      • Lipson E.J.
      • et al.
      Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma.

      Nonmelanoma skin cancer

      Basal cell and squamous cell carcinoma are the two most common types of nonmelanoma skin cancer, and have indications for treatment with the PD-1 inhibitor, cemiplimab.
      • Stonesifer C.J.
      • Djavid A.R.
      • Grimes J.M.
      • et al.
      Immune checkpoint inhibition in non-melanoma skin cancer: a review of current evidence.
      In 2018, cemiplimab was approved for squamous cell carcinoma in patients who were unlikely to receive curable resection.
      • Migden M.R.
      • Rischin D.
      • Schmults C.D.
      • et al.
      PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma.
      In 2021, basal cell carcinoma patients who are intolerant of hedgehog inhibitors were also approved for cemiplimab monotherapy.
      • Stratigos A.J.
      • Sekulic A.
      • Peris K.
      • et al.
      Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.
      Finally, based on results from the Keynote-017, pembrolizumab can be used as first line treatment for recurrent locally advanced tumors in patients with Merkel cell carcinoma.
      • Nghiem P.T.
      • Bhatia S.
      • Lipson E.J.
      • et al.
      PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma.

      Head and neck cancer

      Currently, immunotherapy is approved for use in recurrent unresectable squamous cell carcinoma of the head and neck. The first approval came in 2016 for patient’s refractory to platinum-based chemotherapy.
      • Chow L.Q.M.
      • Haddad R.
      • Gupta S.
      • et al.
      Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort.
      ,
      • Ferris R.L.
      • Blumenschein Jr., G.
      • Fayette J.
      • et al.
      Nivolumab for recurrent squamous-cell carcinoma of the head and neck.
      In 2019, pembrolizumab plus platinum and fluorouracil or pembrolizumab alone (if tumors express PD-L1) was approved as frontline therapy.
      • Burtness B.
      • Harrington K.J.
      • Greil R.
      • et al.
      Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

      Lung cancer

      Small cell lung cancer

      Small cell lung cancer (SCLC) is divided into limited disease (one side of the chest) and extensive disease. Traditionally, extensive-stage small cell lung cancer (ES-SCLC) was treated with platinum plus etoposide.
      • Horn L.
      • Mansfield A.S.
      • Szczęsna A.
      • et al.
      First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.
      In 2018, atezolizumab plus carboplatin and etoposide was approved for patients with ES-SCLC as first line treatment after the Impower133 trial showed longer progression-free and overall survival compared to chemotherapy alone.
      • Horn L.
      • Mansfield A.S.
      • Szczęsna A.
      • et al.
      First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.
      Shortly after, in 2020, the PD-L1 inhibitor durvalumab plus chemotherapy was approved as first line treatment.
      • Paz-Ares L.
      • Dvorkin M.
      • Chen Y.
      • et al.
      Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.

      Non–small-cell lung cancer

      ICB can be used in unresectable non–small-cell lung cancer (NSCLC), in addition to early-stage disease (discussed below). Durvalumab was approved in 2018 for patients with stage III NSCLC following chemoradiation. In comparison with placebo, durvalumab led to improvements in 18-month progression-free survival (27.0% [95% confidence interval {CI}, 19.9-34.5], 44.2% [95% CI, 37.7-50.5]).
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      In patients whose tumors have PD-L1 expression, cemiplimab plus platinum-based chemotherapy was approved in 2021 based on improved outcomes with the addition of cemiplimab to chemotherapy.
      • Akinboro O.
      • Larkins E.
      • Pai-Scherf L.H.
      • et al.
      FDA approval summary: pembrolizumab, Atezolizumab, and Cemiplimab-rwlc as single agents for first-line treatment of advanced/metastatic PD-L1 high NSCLC.

      Excretory system cancer

      Urothelial carcinoma

      Urothelial carcinoma is the most common malignancy in the urinary tract, and approximately 5% of patients develop invasive disease that cannot be managed with surgical resection.
      • Park J.C.
      • Citrin D.E.
      • Agarwal P.K.
      • Apolo A.B.
      Multimodal management of muscle-invasive bladder cancer.
      These patients require cisplatin-based chemotherapy; however, there are patients who are not eligible for this regimen. In 2017, both pembrolizumab and atezolizumab were approved for the treatment of patients with locally advanced urothelial carcinoma who are ineligible for platinum-based therapy.
      • Suzman D.L.
      • Agrawal S.
      • Ning Y.M.
      • et al.
      FDA approval summary: atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin-containing chemotherapy.
      For patients who do undergo platinum-based chemotherapy, avelumab given as maintenance after chemotherapy showed improved overall survival (71.3% [95% CI, 66.0-76.0]) compared to placebo (58.4% [95% CI, 52.7-63.7]), leading to FDA approval for this indication. Lastly, nivolumab is approved for urothelial carcinoma after radical surgical resection for high-risk disease regardless of neoadjuvant treatment regimen.
      • Bajorin D.F.
      • Witjes J.A.
      • Gschwend J.E.
      • et al.
      Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma.

      Renal cell carcinoma

      Renal cell carcinoma (RCC) is generally characterized as chemotherapy-resistant; however, both antiangiogenic agents and ICB have proven effective in RCC. ICB potentiates the effects of vascular endothelial growth factor (VEGF) inhibitors, which are standard-of-care first line therapy for advanced RCC.
      • Escudier B.
      Sunitinib for the management of advanced renal cell carcinoma.
      Combination therapy of the PD-1 inhibitor, pembrolizumab, or PD-L1 inhibitor, avelumab, plus the VEGF inhibitor axitinib has been approved for advanced RCC.
      • Motzer R.J.
      • Penkov K.
      • Haanen J.
      • et al.
      Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      The Clot Lysis Evaluating Accelerated Resolution trial randomized patients with advanced RCC to the VEGF inhibitor lenvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitinib (VEGF inhibitor) alone and showed that pembrolizumab plus lenvatinib improved progression-free survival (median, 23.9 versus 9.2 mo) when compared to sunitinib alone.
      • Motzer R.
      • Alekseev B.
      • Rha S.Y.
      • et al.
      Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
      Additional ICB combinations including those with the CTLA-4 inhibitor, ipilimumab, for advanced RCC have also been approved.
      • Choueiri T.K.
      • Powles T.
      • Burotto M.
      • et al.
      Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.J.
      • Tannir N.M.
      • McDermott D.F.
      • et al.
      Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
      Finally, in patients with high risk disease who have undergone surgical resection, adjuvant pembrolizumab improved disease-free survival compared to placebo alone.
      • Choueiri T.K.
      • Tomczak P.
      • Park S.H.
      • et al.
      Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma.

      Hepatocellular carcinoma

      Hepatocellular carcinoma accounts for approximately 90% of primary liver cancer. The pathogenesis of hepatocellular carcinoma is often related to chronic inflammation due to infection (hepatitis) or steatohepatitis.
      • Donisi C.
      • Puzzoni M.
      • Ziranu P.
      • et al.
      Immune checkpoint inhibitors in the treatment of HCC.
      This inflammation can also be associated with an immunogenic environment, making ICB a potential therapy for this cancer which can be difficult to treat. For patients previously treated with sorafenib, the addition of pembrolizumab as a second-line therapy improved outcomes.
      • Zhu A.X.
      • Finn R.S.
      • Edeline J.
      • et al.
      Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
      In untreated patients with unresectable disease, the combination of atezolizumab plus bevacizumab led to an increase in overall survival at 12 mo (67.2% [95% CI, 61.3-73.1]) compared with sorafenib alone (54.6% [95% CI, 45.2-64.0]).
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.

      Early-stage disease/neoadjuvant use

      As with many new drugs, the first studies of ICB have been in the unresectable and metastatic stages. More recently, ICB has been tested in early-stage disease, with benefits shown in breast, lung, and skin cancers. ICB has approval for use in the neoadjuvant setting in both triple negative breast cancer and NSCLC. The FDA approval for ICB plus chemotherapy for neoadjuvant use in triple negative breast cancer patients with high-risk stage II and III disease came on the heels of the Keynote 522 trial results which showed improved pathologic complete response (pCR) and event free survival (EFS) (by 7 mo) with ICB plus chemotherapy compared to chemotherapy alone.
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      The PD-1 inhibitor, nivolumab, is approved for use in early stage NSCLC based on a study showing improved pCR and EFS with the addition of nivolumab to chemotherapy.
      • Forde P.M.
      • Spicer J.
      • Lu S.
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      In the adjuvant setting, atezolizumab is approved for stage 1B–IIIA non-small-cell lung cancer following standard chemotherapy.
      • Felip E.
      • Altorki N.
      • Zhou C.
      • et al.
      Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
      Lastly, pembrolizumab has also been approved in the adjuvant setting for 1 y following surgical resection in patients with stage IIB or IIC melanoma.
      • Luke J.J.
      • Rutkowski P.
      • Queirolo P.
      • et al.
      Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.

      Checkpoint Blockade Toxicity

      ICB has a unique side-effect profile related to its mechanism of action. The activation of T-cells that occurs with ICB treatment can damage off-target tissues. Toxicities from ICB are called immune-related adverse events (irAEs). The overall rate of any toxicity from immunotherapy ranges from 70% to 80% for anti-CTLA-4 and anti-PD-1/PD-L1 therapies (and even higher with dual therapy).
      • Boutros C.
      • Tarhini A.
      • Routier E.
      • et al.
      Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.
      • Wolchok J.D.
      • Chiarion-Sileni V.
      • Gonzalez R.
      Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
      • Wolchok J.D.
      • Rollin L.
      • Larkin J.
      Nivolumab and ipilimumab in advanced melanoma.
      Up to almost half of patients in published studies using ICB discontinued treatment at some point due to irAEs.
      • Kumar V.
      • Chaudhary N.
      • Garg M.
      • Floudas C.S.
      • Soni P.
      • Chandra A.B.
      Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy.
      • Friedman C.F.
      • Proverbs-Singh T.A.
      • Postow M.A.
      • et al.
      Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review.
      The incidence of fatal irAEs is between 0.3% and 1.3%,
      • Wang D.Y.
      • Salem J.E.
      • Cohen J.V.
      • et al.
      Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.
      which is slightly lower than most conventional chemotherapy and targeted therapy regimens. It is imperative that surgeons be aware of potential complications from immunotherapy. IrAEs can present within weeks after starting therapy (most commonly) but also can present months or years later, even after therapy has been stopped.
      • Boutros C.
      • Tarhini A.
      • Routier E.
      • et al.
      Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.
      ,
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      As ICB use in the neoadjuvant setting becomes more common, surgeons will become increasingly responsible for recognizing toxicities. As the prevalence of ICB increases, early identification is a key to successful management.

      Mechanism of immune checkpoint blockade toxicity

      The CTLA-4 and PD-1/PD-L1 checkpoint molecules restrain T-cell function at different stages. Blockade of CTLA-4 works on T-cells proximally in the activation pathway resulting in cessation of proliferation and activation of T-cells.
      • Ribas A.
      • Wolchok J.D.
      Cancer immunotherapy using checkpoint blockade.
      PD-1 restrains T-cells more distally and in peripheral tissues when it is upregulated due to inflammation, as is the case in the tumor microenvironment.
      • Baumeister S.H.
      • Freeman G.J.
      • Dranoff G.
      • Sharpe A.H.
      Coinhibitory pathways in immunotherapy for cancer.
      ,
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      While toxicity in blockade of either pathway is the result of auto-reactive T-cells, antibodies, or cytokines which are released by the activated T-cells, the differing sites of activity of these checkpoint molecules result in different patterns of toxicity. Anti-CTLA-4 toxicity is often more severe and more likely to present as colitis or hypophysitis compared to anti-PD-1/anti-PD-L1 toxicity, which more commonly presents as pneumonitis and thyroiditis.
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      Fatal toxicity also tends to differ depending upon the agent used. Colitis is the most frequent cause of death in patients treated with anti-CTLA-4. Pneumonitis followed by hepatitis and neurotoxic events are the most common cause of anti-PD-1/anti-PD-L1 related death.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.

      Common immune checkpoint blockade toxicities

      Not surprisingly, given the ubiquity of T-cells in the human body, nearly all organ systems can be adversely impacted by ICB (Table 2). Unlike patients treated with conventional cytotoxic chemotherapy, hematologic related events are much less common in patients treated with ICB. Autoimmune hemolytic anemia, autoimmune thrombocytopenia, acquired hemophilia A, and thrombotic thrombocytopenic purpura have all been reported as rare events.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
      Cutaneous toxicities on the other hand, are extremely common and up to half of all patients treated with ICB experience a cutaneous irAE. The most common skin irAEs are rash, pruritus and vitiligo.
      • Minkis K.
      • Garden B.C.
      • Wu S.
      • Pulitzer M.P.
      • Lacouture M.E.
      The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis.
      Rarer cutaneous irAEs include ulcerative or bullous dermatitis, urticaria, xerosis, hyperhidrosis, changes in hair, and lupus-like reactions.
      • Belum V.R.
      • Benhuri B.
      • Postow M.A.
      • et al.
      Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.
      • Trinidad C.
      • Nelson K.C.
      • Glitza Oliva I.C.
      • et al.
      Dermatologic toxicity from immune checkpoint blockade therapy with an interstitial granulomatous pattern.
      • Weber J.S.
      • Dummer R.
      • de Pril V.
      • Lebbe C.
      • Hodi F.S.
      Investigators MDX
      Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma.
      Patients with a personal or family history of psoriasis may also experience relapse, worsening, or emergence of psoriatic skin changes.
      • Voudouri D.
      • Nikolaou V.
      • Laschos K.
      • et al.
      Anti-PD1/PDL1 induced psoriasis.
      Table 2Potential immune-related adverse events (irAEs) related to immune checkpoint blockade.
      Organ systemirAEs reported in literature
      NeurologicEncephalitis, myasthenia gravis or myositis and Guillain-Barre or Guillain-Barre-like syndrome, cerebellar ataxia, retinopathy, peripheral neuropathies, disorders of the neuromuscular junction, asymmetric mononeuritis multiplex
      OcularUveitis, dry eyes
      EndocrineHypophysitis, primary adrenal insufficiency, hypothyroidism, hypoparathyroidism, type I diabetes
      CardiacCardiac myositis
      PulmonaryPneumonitis, cryptogenic organizing pneumonia, sarcoid-like lung disease, hypersensitivity pneumonitis, interstitial pneumonia, and even acute respiratory distress syndrome
      GastrointestinalDiarrhea, colitis, hepatitis, and acute liver failure
      RenalAcute interstitial nephritis and lupus nephritis
      SkinRash, pruritus, and vitiligo, ulcerative or bullous dermatitis, urticaria, xerosis, hyperhidrosis, changes in hair, lupus-like reactions, and psoriasis relapse
      RheumatologicArthralgia, myalgia, inflammatory arthritis, vasculitis, and myositis
      HematologicAutoimmune hemolytic anemia, autoimmune thrombocytopenia, acquired hemophilia A, and thrombotic thrombocytopenic purpura
      Endocrinopathies are relatively common irAEs and are different than adverse events typically seen with traditional cytotoxic chemotherapy. Hypophysitis, or inflammation of the pituitary gland, occurs in up to 12%-13% of patients treated with ICB.
      • Cukier P.
      • Santini F.C.
      • Scarant M.
      • Hoff A.O.
      Endocrine side effects of cancer immunotherapy.
      Hypophysitis may have a vague presentation of headache and fatigue, and therefore it is imperative clinicians are aware of this irAE which occurs more frequently in elderly, male patients, and those treated with anti-CTLA-4 or dual ICB. Hypophysitis results in multiple hormone deficiencies, most commonly central hypothyroidism and adrenal insufficiency.
      • Cukier P.
      • Santini F.C.
      • Scarant M.
      • Hoff A.O.
      Endocrine side effects of cancer immunotherapy.
      Patients may also suffer from a variety of other endocrinopathies, including secondary hypothyroidism (4%-19.5%), primary adrenal insufficiency (approximately 1%), hypoparathyroidism, and type I diabetes (<1%) which so far has only been reported in those treated with anti-PD-1/PDL-1 therapy.
      • Cukier P.
      • Santini F.C.
      • Scarant M.
      • Hoff A.O.
      Endocrine side effects of cancer immunotherapy.
      Cardiopulmonary toxicity has the potential to be life-threatening. ICB-associated myocarditis is a severe complication that occurs in 1.4% of patients and has a high risk of death. It is the most fatal irAE and is the cause of almost 40% of all deaths related to ICB.
      • Varricchi G.
      • Galdiero M.R.
      • Marone G.
      • et al.
      Cardiotoxicity of immune checkpoint inhibitors.
      Cardiac toxicity more commonly occurs in patients treated with dual ICB. ICB-associated myocarditis has a range of presentations including asymptomatic myocardial infarction, chest pain, shortness of breath, or acute circulatory collapse.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
      Immune-related pneumonitis is also a life-threatening complication that occurs in 1%-5% of patients treated with ICB.
      • Naidoo J.
      • Wang X.
      • Woo K.M.
      • et al.
      Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
      Pulmonary irAEs are more common in patients being treated for NSCLC than other diseases and present most commonly as cryptogenic organizing pneumonia, sarcoid-like lung disease, hypersensitivity pneumonitis, interstitial pneumonia, or even acute respiratory distress syndrome.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
      Toxicity impacting the lower gastrointestinal tract occurs in 10%-20% of patients and ranges from mild diarrhea to colitis that can be severe, mimicking inflammatory bowel disease.
      • Dougan M.
      Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal tract.
      Endoscopy and biopsy are often required for diagnosis.
      • Som A.
      • Mandaliya R.
      • Alsaadi D.
      • et al.
      Immune checkpoint inhibitor-induced colitis: a comprehensive review.
      Hepatitis may also occur in 5%-10% of patients treated with ICB and ranges from mild elevations in liver function tests to hyperbilirubinemia and coagulopathy and rarely, acute liver failure.
      • Suzman D.L.
      • Pelosof L.
      • Rosenberg A.
      • Avigan M.I.
      Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents.
      Other, less common irAEs involve the neurologic, ocular, rheumatologic, and renal systems. Neurologic irAEs have a wide range of manifestations including encephalitis, myasthenia gravis or myositis, and Guillain–Barre or Guillain–Barre-like syndromes as well as other rare complications such as cerebellar ataxia, retinopathy, peripheral neuropathies, disorders of the neuromuscular junction, and asymmetric mononeuritis multiplex.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
      Uveitis and dry eyes are the most common reported irAEs in those treated with ICB, based on a review of 11 trials.
      • Abdel-Rahman O.
      • Oweira H.
      • Petrausch U.
      • et al.
      Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review.
      In a systematic review of the literature, Capelli et al. identified arthralgia and myalgias as common irAEs, occurring in up to 45% of patients.
      • Cappelli L.C.
      • Gutierrez A.K.
      • Bingham 3rd, C.O.
      • Shah A.A.
      Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature.
      Case reports detail incidences of inflammatory arthritis, vasculitis, lupus nephritis, and myositis though the connection to ICB is less clear. Acute interstitial nephritis is the most common irAE to impact the kidney and is likely caused by the loss of self-tolerance.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.

      Timeline of ICB toxicity

      IrAEs are generally graded based on the National Cancer Institute's Common Terminology Criteria for Adverse Events. Grades 1 and 2 are considered mild, and grades 3 and 4 are serious. The majority of serious (grade 3 or 4) irAEs occur within 8-12 wk of starting treatment. Dermatologic manifestations typically have the earliest onset, followed by hepatotoxicity, which tends to occur earlier than 8-12 wk. Rheumatologic and renal irAEs often present later from the initiation of treatment.
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
      Fatal toxicities have a rapid onset, particularly when compared to those caused by other drugs used in the treatment of cancer, with a median time to onset of a fatal toxic event at 14.5 d (for dual ICB therapy) and 40 in single-agent ICB therapy.
      • Hellmann M.D.
      • Ciuleanu T.E.
      • Pluzanski A.
      • et al.
      Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.
      It is important to note that late-onset and long-lasting irAEs are likely under-reported and relatively common.
      • Ghisoni E.
      • Wicky A.
      • Bouchaab H.
      • et al.
      Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: an overlooked aspect in immunotherapy.
      This point is particularly important for the practicing surgeon, who may be the first to diagnose an irAE in a patient treated with neoadjuvant ICB.

      Monitoring and treatment of ICB toxicity

      Consensus guidelines have been developed to help screen for and treat irAEs.
      • Puzanov I.
      • Diab A.
      • Abdallah K.
      • et al.
      Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working group.
      Prior to initiating ICB, consideration should be given to obtaining a complete history and physical exam with focus on autoimmune diseases and bowel habits, as well as baseline oxygen saturation, and on dermatologic and mucosal exam. Baseline bloodwork should include complete blood count, comprehensive metabolic panel, thyroid stimulating hormone, HbA1c, Free T4, total creatine kinase, fasting lipids, hepatitis screen, electrocardiogram, and troponin at baseline and weekly for 6 wk.
      • Puzanov I.
      • Diab A.
      • Abdallah K.
      • et al.
      Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working group.
      Patients should be educated about irAEs, and the treatment team will need to be familiar with irAEs as rapid identification can be crucial in preventing mortality from potentially fatal irAEs.
      The main pillars of treatment for irAEs are withdrawal of ICB and treatment with steroids and other immunosuppressive medications.
      • Friedman C.F.
      • Proverbs-Singh T.A.
      • Postow M.A.
      • et al.
      Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review.
      • Weber J.S.
      • Yang J.C.
      • Atkins M.B.
      • Disis M.L.
      Toxicities of immunotherapy for the practitioner.
      For patients with grade 1 irAEs, steroids are usually not indicated, and treatment can be continued. For those with grade 2 irAEs, oral and potentially intravenous steroids may be used. Therapy should be held while steroids are given and until toxicity reaches grade 1 level. Patients with grade 3 or 4 toxicities should be treated with intravenous steroids and immunotherapy should be held. For grade 3 toxicities that do not resolve in 4-6 wk and any grade 4 toxicity, immunotherapy should be permanently discontinued. Patients with severe irAEs who fail to improve on steroids may benefit from the addition of an added immunosuppressive agent, such as infliximab. Patients on steroids should be placed on proton pump inhibitors and for those on steroids >3 wk, prophylaxis against pneumocystis pneumonia should be given.
      • Puzanov I.
      • Diab A.
      • Abdallah K.
      • et al.
      Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working group.
      New drugs are also in development, such as vedolizumab, an integrin receptor antagonist that acts specifically on the gut.
      Surgeons should also be aware that immune-related colitis can be quite severe and may require endoscopy and biopsy for diagnosis.
      • Som A.
      • Mandaliya R.
      • Alsaadi D.
      • et al.
      Immune checkpoint inhibitor-induced colitis: a comprehensive review.
      Surgical intervention is only necessary in cases of perforation, abscesses that cannot be drained percutaneously, toxic megacolon, intractable bleeding, or treatment refractory disease.
      • Helmink B.A.
      • Roland C.L.
      • Kiernan C.M.
      • Wargo J.A.
      Toxicity of immune checkpoint inhibitors: considerations for the surgeon.

      ICB toxicity and its relationship to response to therapy

      The occurrence of an irAE is evidence that the patient's immune system has been activated. This has led some to postulate that those with irAEs may have better immune activation and therefore a better treatment response. Some studies have demonstrated an association between irAEs and antitumor response as well as an increase in survival in those with more irAEs.
      • Maher V.E.
      • Fernandes L.L.
      • Weinstock C.
      • et al.
      Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody.
      • Eggermont A.M.M.
      • Kicinski M.
      • Blank C.U.
      • et al.
      Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial.
      • Shankar B.
      • Zhang J.
      • Naqash A.R.
      Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer.
      However, other studies have shown that specific irAEs may be associated with worse outcomes. The implication that irAEs are a sign of a productive immune response against tumor remains controversial. This is due to concerns about statistical analyses used in studies that support this and the challenges in diagnosing irAEs and also attributing clinical findings to ICB.
      • Conroy M.
      • Naidoo J.
      Immune-related adverse events and the balancing act of immunotherapy.

      Complications and use of immunotherapy in the neoadjuvant setting

      Immunotherapy continues to gain approval for use in the neoadjuvant setting and irAEs can happen in the perioperative setting. The onus is therefore on the surgeon, to suspect and diagnose irAEs, which as described above, can be both life-threatening and at the same time, have a vague presentation.
      Data are limited on the optimal timing of surgery for patients treated with neoadjuvant ICB. Studies from patients with metastatic cancer who subsequently underwent surgery after treatment in the neoadjuvant setting show no specific complications related to the timing of ICB
      • Bott M.J.
      • Cools-Lartigue J.
      • Tan K.S.
      • et al.
      Safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors.
      • Elias A.W.
      • Kasi P.W.
      • Stauffer J.A.
      • et al.
      The feasibility and safety of surgery in patients receiving immune checkpoint inhibitors: a retrospective study.
      • Gyorki D.E.
      • Yuan J.
      • Mu Z.
      • et al.
      Immunological insights from patients undergoing surgery on ipilimumab for metastatic melanoma.
      • Amaria R.N.
      • Reddy S.M.
      • Tawbi H.A.
      • et al.
      Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
      • Blank C.U.
      • Rozeman E.A.
      • Fanchi L.F.
      • et al.
      Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.
      • Carthon B.C.
      • Wolchok J.D.
      • Yuan J.
      Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
      • Forde P.M.
      • Chaft J.E.
      • Pardoll D.M.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      and that patients undergo surgery as soon as 2 wk post-treatment. Those who experience more severe irAE are more likely to experience delays. Many advocate for preoperative work-up to evaluate for irAEs, particularly adrenal insufficiency, in those who have completed neoadjuvant immunotherapy.
      • Helmink B.A.
      • Roland C.L.
      • Kiernan C.M.
      • Wargo J.A.
      Toxicity of immune checkpoint inhibitors: considerations for the surgeon.

      The future of immune checkpoint blockade

      While the approval of ICB has been a major landmark for some diseases, work is ongoing to discover combination therapies to improve response rates, to make certain tumors immunologically “hot” so they will respond to ICB, and to identify biomarkers to predict which patients will respond to ICB. In addition to PD-1/PD-L1, checkpoint molecules adenosine A2A receptor, LAG-3, and TIM3 are under investigation as potential coinhibitors. Several other molecules, such as GITR, 4-1BB, OX40, and CD27, are being evaluated as costimulatory targets to add to ICB.
      • Hahn A.W.
      • Gill D.M.
      • Pal S.K.
      • Agarwal N.
      The future of immune checkpoint cancer therapy after PD-1 and CTLA-4.
      Other studies have focused on making immunologically cold tumors hot by enhancing T-cell priming and activation (oncolytic viruses, chemotherapy, radiotherapy, thermal ablation, epigenetic modification inhibitors, photothermal therapy, and photodynamic therapy), expanding T-cells (adoptive cellular therapy and vaccines) and improving T-cell trafficking to and infiltration into the tumor microenvironment (antiangiogenic therapy, TGFβ inhibitor, CXCR4 inhibitor, epigenetic modification inhibitor, and oncogenic pathway inhibitors).
      • Liu Y.T.
      • Sun Z.J.
      Turning cold tumors into hot tumors by improving T-cell infiltration.
      Finally, in addition to the known biomarkers PD-L1, tumor mutational burden, MSI, and MMR deficiency, efforts are underway to uncover additional biomarkers of response including circulating and microbiome biomarkers.
      • Lei Y.
      • Li X.
      • Huang Q.
      • Zheng X.
      • Liu M.
      Progress and challenges of predictive biomarkers for immune checkpoint blockade.
      As these advances move to the clinics, the care of cancer patients will become even more nuanced. Surgeons will need to remain aware of how new therapies influence the ordering of treatment and take shared ownership over recognizing and addressing irAEs.

      Author Contributions

      SDC and XB contributed to conceptualization; SDC and XB contributed to writing–original draft preparation; XB, SDC, and PS contributed to writing–review and editing; All authors have read and agreed to the published version of the manuscript.

      Disclosure

      Dr. Downs-Canner is a member of the Editorial Board of the Journal of Surgical Research; as such, she was excluded from the entire peer-review and editorial process for this manuscript.

      Funding

      This research received no external funding.

      References

        • Abbas A.K.
        • Lichtman A.H.
        • Pillai S.
        Cellular and Molecular Immunology.
        Elsevier, Philadelphia, PA2018
        • Delves P.J.
        • Roitt I.M.
        The immune system. Second of two parts.
        N Engl J Med. 2000; 343: 108-117
        • Hillion S.
        • Arleevskaya M.I.
        • Blanco P.
        • et al.
        The innate part of the adaptive immune system.
        Clin Rev Allergy Immunol. 2020; 58: 151-154
        • Raskov H.
        • Orhan A.
        • Christensen J.P.
        • Gogenur I.
        Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy.
        Br J Cancer. 2021; 124: 359-367
        • Oshi M.
        • Asaoka M.
        • Tokumaru Y.
        • et al.
        CD8 T cell score as a prognostic biomarker for triple negative breast cancer.
        Int J Mol Sci. 2020; 21: 6968
        • Blessin N.C.
        • Li W.
        • Mandelkow T.
        • et al.
        Prognostic role of proliferating CD8(+) cytotoxic Tcells in human cancers.
        Cell Oncol (Dordr). 2021; 44: 793-803
        • Zhang N.
        • Bevan M.J.
        CD8(+) T cells: foot soldiers of the immune system.
        Immunity. 2011; 35: 161-168
        • Vinay D.S.
        • Ryan E.P.
        • Pawelec G.
        • et al.
        Immune evasion in cancer: mechanistic basis and therapeutic strategies.
        Semin Cancer Biol. 2015; 35: S185-S198
        • Azuma M.
        Co-Signal molecules in T-cell activation : historical overview and perspective.
        Adv Exp Med Biol. 2019; 1189: 3-23
        • Ribas A.
        • Wolchok J.D.
        Cancer immunotherapy using checkpoint blockade.
        Science. 2018; 359: 1350-1355
        • Kalia V.
        • Yuzefpolskiy Y.
        • Vegaraju A.
        • et al.
        Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice.
        Sci Transl Med. 2021; 13: eaba6006
        • Baumeister S.H.
        • Freeman G.J.
        • Dranoff G.
        • Sharpe A.H.
        Coinhibitory pathways in immunotherapy for cancer.
        Annu Rev Immunol. 2016; 34: 539-573
        • Yi M.
        • Zhu S.
        • Ge K.
        • Wu K.
        Combination strategies with PD-1/PD-L1 blockade: current advances and future directions.
        Mol Cancer. 2022; 21: 28
        • Wu Q.
        • Jiang L.
        • Li S.C.
        • He Q.J.
        • Yang B.
        • Cao J.
        Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway.
        Acta Pharmacol Sin. 2021; 42: 1-9
        • Maruhashi T.
        • Sugiura D.
        • Okazaki I.M.
        • Okazaki T.
        LAG-3: from molecular functions to clinical applications.
        J Immunother Cancer. 2020; 8: e001014
        • Fishel R.
        Mismatch repair.
        J Biol Chem. 2015; 290: 26395-26403
        • Sahin I.H.
        • Akce M.
        • Alese O.
        • et al.
        Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms.
        Br J Cancer. 2019; 121: 809-818
        • André T.
        • Shiu K.K.
        • Kim T.W.
        • et al.
        Pembrolizumab in microsatellite-instability-high advanced colorectal cancer.
        N Engl J Med. 2020; 383: 2207-2218
        • Pirs B.
        • Skof E.
        • Smrkolj V.
        • Smrkolj S.
        Overview of immune checkpoint inhibitors in gynecological cancer treatment.
        Cancers (Basel). 2022; 14: 631
        • Hansen A.R.
        • Massard C.
        • Ott P.A.
        • et al.
        Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.
        Ann Oncol. 2018; 29: 1807-1813
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Bonneville R.
        • Krook M.A.
        • Kautto E.A.
        • et al.
        Landscape of microsatellite instability across 39 cancer types.
        JCO Precis Oncol. 2017; 2017 (PO.17.00073)
        • Roudko V.
        • Cimen Bozkus C.
        • Greenbaum B.
        • Lucas A.
        • Samstein R.
        • Bhardwaj V.
        Lynch syndrome and MSI-H cancers: from mechanisms to “Off-The-Shelf” cancer vaccines.
        Front Immunol. 2021; 12: 757804
        • Therkildsen C.
        • Jensen L.H.
        • Rasmussen M.
        • Bernstein I.
        An update on immune checkpoint therapy for the treatment of Lynch syndrome.
        Clin Exp Gastroenterol. 2021; 14: 181-197
        • Cercek A.
        • Lumish M.
        • Sinopoli J.
        • et al.
        PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer.
        N Engl J Med. 2022; 386: 2363-2376
        • Huang A.C.
        • Zappasodi R.
        A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance.
        Nat Immunol. 2022; 23: 660-670
        • Hodi F.S.
        • O’Day S.J.
        • McDermott D.F.
        • et al.
        Improved survival with ipilimumab in patients with metastatic melanoma.
        N Engl J Med. 2010; 363: 711-723
        • Larkin J.
        • Chiarion-Sileni V.
        • Gonzalez R.
        • et al.
        Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
        N Engl J Med. 2015; 373: 23-34
        • Tawbi H.A.
        • Schadendorf D.
        • Lipson E.J.
        • et al.
        Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma.
        N Engl J Med. 2022; 386: 24-34
        • Stonesifer C.J.
        • Djavid A.R.
        • Grimes J.M.
        • et al.
        Immune checkpoint inhibition in non-melanoma skin cancer: a review of current evidence.
        Front Oncol. 2021; 11: 734354
        • Migden M.R.
        • Rischin D.
        • Schmults C.D.
        • et al.
        PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma.
        N Engl J Med. 2018; 379: 341-351
        • Stratigos A.J.
        • Sekulic A.
        • Peris K.
        • et al.
        Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.
        Lancet Oncol. 2021; 22: 848-857
        • Nghiem P.T.
        • Bhatia S.
        • Lipson E.J.
        • et al.
        PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma.
        N Engl J Med. 2016; 374: 2542-2552
        • Chow L.Q.M.
        • Haddad R.
        • Gupta S.
        • et al.
        Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort.
        J Clin Oncol. 2016; 34: 3838-3845
        • Ferris R.L.
        • Blumenschein Jr., G.
        • Fayette J.
        • et al.
        Nivolumab for recurrent squamous-cell carcinoma of the head and neck.
        N Engl J Med. 2016; 375: 1856-1867
        • Burtness B.
        • Harrington K.J.
        • Greil R.
        • et al.
        Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.
        Lancet. 2019; 394: 1915-1928
        • Horn L.
        • Mansfield A.S.
        • Szczęsna A.
        • et al.
        First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.
        N Engl J Med. 2018; 379: 2220-2229
        • Paz-Ares L.
        • Dvorkin M.
        • Chen Y.
        • et al.
        Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
        Lancet. 2019; 394: 1929-1939
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • et al.
        Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
        N Engl J Med. 2017; 377: 1919-1929
        • Akinboro O.
        • Larkins E.
        • Pai-Scherf L.H.
        • et al.
        FDA approval summary: pembrolizumab, Atezolizumab, and Cemiplimab-rwlc as single agents for first-line treatment of advanced/metastatic PD-L1 high NSCLC.
        Clin Cancer Res. 2022; 28: 2221-2228
        • Park J.C.
        • Citrin D.E.
        • Agarwal P.K.
        • Apolo A.B.
        Multimodal management of muscle-invasive bladder cancer.
        Curr Probl Cancer. 2014; 38: 80-108
        • Suzman D.L.
        • Agrawal S.
        • Ning Y.M.
        • et al.
        FDA approval summary: atezolizumab or pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin-containing chemotherapy.
        Oncologist. 2019; 24: 563-569
        • Bajorin D.F.
        • Witjes J.A.
        • Gschwend J.E.
        • et al.
        Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma.
        N Engl J Med. 2021; 384: 2102-2114
        • Escudier B.
        Sunitinib for the management of advanced renal cell carcinoma.
        Expert Rev Anticancer Ther. 2010; 10: 305-317
        • Motzer R.J.
        • Penkov K.
        • Haanen J.
        • et al.
        Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2019; 380: 1103-1115
        • Rini B.I.
        • Plimack E.R.
        • Stus V.
        • et al.
        Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2019; 380: 1116-1127
        • Motzer R.
        • Alekseev B.
        • Rha S.Y.
        • et al.
        Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma.
        N Engl J Med. 2021; 384: 1289-1300
        • Choueiri T.K.
        • Powles T.
        • Burotto M.
        • et al.
        Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma.
        N Engl J Med. 2021; 384: 829-841
        • Motzer R.J.
        • Tannir N.M.
        • McDermott D.F.
        • et al.
        Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
        N Engl J Med. 2018; 378: 1277-1290
        • Choueiri T.K.
        • Tomczak P.
        • Park S.H.
        • et al.
        Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma.
        N Engl J Med. 2021; 385: 683-694
        • Donisi C.
        • Puzzoni M.
        • Ziranu P.
        • et al.
        Immune checkpoint inhibitors in the treatment of HCC.
        Front Oncol. 2020; 10: 601240
        • Zhu A.X.
        • Finn R.S.
        • Edeline J.
        • et al.
        Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
        Lancet Oncol. 2018; 19: 940-952
        • Finn R.S.
        • Qin S.
        • Ikeda M.
        • et al.
        Pembrolizumab for early triple-negative breast cancer.
        N Engl J Med. 2020; 382: 1894-1905
        • Schmid P.
        • Cortes J.
        • Pusztai L.
        • et al.
        Pembrolizumab for early triple-negative breast cancer.
        N Engl J Med. 2020; 382: 810-821
        • Forde P.M.
        • Spicer J.
        • Lu S.
        • et al.
        Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
        N Engl J Med. 2020; 386: 1973-1985
        • Felip E.
        • Altorki N.
        • Zhou C.
        • et al.
        Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
        Lancet. 2021; 398: 1344-1357
        • Luke J.J.
        • Rutkowski P.
        • Queirolo P.
        • et al.
        Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.
        Lancet. 2022; 399: 1718-1729
        • Boutros C.
        • Tarhini A.
        • Routier E.
        • et al.
        Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination.
        Nat Rev Clin Oncol. 2016; 13: 473-486
        • Wolchok J.D.
        • Chiarion-Sileni V.
        • Gonzalez R.
        Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
        N Engl J Med. 2017; 377: 1345-1356
        • Wolchok J.D.
        • Rollin L.
        • Larkin J.
        Nivolumab and ipilimumab in advanced melanoma.
        N Engl J Med. 2017; 377: 2503-2504
        • Kumar V.
        • Chaudhary N.
        • Garg M.
        • Floudas C.S.
        • Soni P.
        • Chandra A.B.
        Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy.
        Front Pharmacol. 2017; 49https://doi.org/10.3389/fphar.2017.00049
        • Friedman C.F.
        • Proverbs-Singh T.A.
        • Postow M.A.
        • et al.
        Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review.
        JAMA Oncol. 2016; 2: 1346-1353
        • Wang D.Y.
        • Salem J.E.
        • Cohen J.V.
        • et al.
        Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.
        JAMA Oncol. 2018; 2: 1721-1728
        • Postow M.A.
        • Sidlow R.
        • Hellmann M.D.
        Immune-related adverse events associated with immune checkpoint blockade.
        N Engl J Med. 2018; 378: 158-168
        • Martins F.
        • Sofiya L.
        • Sykiotis G.P.
        • et al.
        Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
        Nat Rev Clin Oncol. 2019; 16: 563-580
        • Minkis K.
        • Garden B.C.
        • Wu S.
        • Pulitzer M.P.
        • Lacouture M.E.
        The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis.
        J Am Acad Dermatol. 2013; 69: e121-e128
        • Belum V.R.
        • Benhuri B.
        • Postow M.A.
        • et al.
        Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.
        Eur J Cancer. 2016; 60: 12-25
        • Trinidad C.
        • Nelson K.C.
        • Glitza Oliva I.C.
        • et al.
        Dermatologic toxicity from immune checkpoint blockade therapy with an interstitial granulomatous pattern.
        J Cutan Pathol. 2018; 45: 504-507
        • Weber J.S.
        • Dummer R.
        • de Pril V.
        • Lebbe C.
        • Hodi F.S.
        • Investigators MDX
        Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma.
        Cancer. 2013; 119: 1657-1682
        • Voudouri D.
        • Nikolaou V.
        • Laschos K.
        • et al.
        Anti-PD1/PDL1 induced psoriasis.
        Curr Probl Cancer. 2017; 41: 407-412
        • Cukier P.
        • Santini F.C.
        • Scarant M.
        • Hoff A.O.
        Endocrine side effects of cancer immunotherapy.
        Endocr Relat Cancer. 2017; 24: T331-T347
        • Varricchi G.
        • Galdiero M.R.
        • Marone G.
        • et al.
        Cardiotoxicity of immune checkpoint inhibitors.
        ESMO Open. 2017; 2: e000247
        • Naidoo J.
        • Wang X.
        • Woo K.M.
        • et al.
        Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.
        J Clin Oncol. 2017; 35: 709-717
        • Dougan M.
        Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal tract.
        Front Immunol. 2017; 8: 1547
        • Som A.
        • Mandaliya R.
        • Alsaadi D.
        • et al.
        Immune checkpoint inhibitor-induced colitis: a comprehensive review.
        World J Clin Cases. 2019; 7: 405-418
        • Suzman D.L.
        • Pelosof L.
        • Rosenberg A.
        • Avigan M.I.
        Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents.
        Liver Int. 2018; 38: 976-987
        • Abdel-Rahman O.
        • Oweira H.
        • Petrausch U.
        • et al.
        Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review.
        Expert Rev Anticancer Ther. 2017; 17: 387-394
        • Cappelli L.C.
        • Gutierrez A.K.
        • Bingham 3rd, C.O.
        • Shah A.A.
        Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature.
        Arthritis Care Res (Hoboken). 2017; 69: 1751-1763
        • Hellmann M.D.
        • Ciuleanu T.E.
        • Pluzanski A.
        • et al.
        Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.
        N Engl J Med. 2018; 378: 2093-2104
        • Ghisoni E.
        • Wicky A.
        • Bouchaab H.
        • et al.
        Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: an overlooked aspect in immunotherapy.
        Eur J Cancer. 2021; 149: 153-164
        • Puzanov I.
        • Diab A.
        • Abdallah K.
        • et al.
        Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) toxicity management working group.
        J Immunother Cancer. 2017; 5: 95
        • Weber J.S.
        • Yang J.C.
        • Atkins M.B.
        • Disis M.L.
        Toxicities of immunotherapy for the practitioner.
        J Clin Oncol. 2015; 33: 2092-2099
        • Helmink B.A.
        • Roland C.L.
        • Kiernan C.M.
        • Wargo J.A.
        Toxicity of immune checkpoint inhibitors: considerations for the surgeon.
        Ann Surg Oncol. 2020; 27: 1533-1545
        • Maher V.E.
        • Fernandes L.L.
        • Weinstock C.
        • et al.
        Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody.
        J Clin Oncol. 2020; 37: 2730-2737
        • Eggermont A.M.M.
        • Kicinski M.
        • Blank C.U.
        • et al.
        Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial.
        JAMA Oncol. 2020; 6: 519-527
        • Shankar B.
        • Zhang J.
        • Naqash A.R.
        Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer.
        JAMA Oncol. 2020; 6: 1952-1956
        • Conroy M.
        • Naidoo J.
        Immune-related adverse events and the balancing act of immunotherapy.
        Nat Commun. 2022; 13: 392
        • Bott M.J.
        • Cools-Lartigue J.
        • Tan K.S.
        • et al.
        Safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors.
        Ann Thorac Surg. 2018; 106: 178-183
        • Elias A.W.
        • Kasi P.W.
        • Stauffer J.A.
        • et al.
        The feasibility and safety of surgery in patients receiving immune checkpoint inhibitors: a retrospective study.
        Front Oncol. 2017; 7: 121
        • Gyorki D.E.
        • Yuan J.
        • Mu Z.
        • et al.
        Immunological insights from patients undergoing surgery on ipilimumab for metastatic melanoma.
        Ann Surg Oncol. 2013; 20: 3106-3111
        • Amaria R.N.
        • Reddy S.M.
        • Tawbi H.A.
        • et al.
        Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
        Nat Med. 2018; 24: 1649-1654
        • Blank C.U.
        • Rozeman E.A.
        • Fanchi L.F.
        • et al.
        Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.
        Nat Med. 2018; 24: 1655-1661
        • Carthon B.C.
        • Wolchok J.D.
        • Yuan J.
        Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
        Clin Cancer Res. 2010; 16: 2861-2871
        • Forde P.M.
        • Chaft J.E.
        • Pardoll D.M.
        • et al.
        Neoadjuvant PD-1 blockade in resectable lung cancer.
        N Engl J Med. 2018; 379: e14
        • Hahn A.W.
        • Gill D.M.
        • Pal S.K.
        • Agarwal N.
        The future of immune checkpoint cancer therapy after PD-1 and CTLA-4.
        Immunotherapy. 2017; 9: 681-692
        • Liu Y.T.
        • Sun Z.J.
        Turning cold tumors into hot tumors by improving T-cell infiltration.
        Theranostics. 2021; 11: 5365-5386
        • Lei Y.
        • Li X.
        • Huang Q.
        • Zheng X.
        • Liu M.
        Progress and challenges of predictive biomarkers for immune checkpoint blockade.
        Front Oncol. 2021; 11: 617335