Abstract
Background
The generation of long-term durable tumor immunity and prolonged disease-free survival
depends on the ability to generate and support CD8+ central memory T-cells. Microsatellite-stable
colon cancer is resistant to currently available immunotherapies; thus, development
of novel mechanisms to increase both lymphocyte infiltration and central memory formation
are needed to improve outcomes in these patients. We have previously demonstrated
that both interleukin-2 (IL-2) and LIGHT (TNFSF14) independently enhance antitumor
immune responses and hypothesize that combination immunotherapy may increase the CD8+
central memory T-cell response.
Methods
Murine colorectal cancer tumors were established in syngeneic mice. Tumors were treated
with control, soluble, or liposomal IL-2 at established intervals. A subset of animal
tumors overexpressed tumor necrosis superfamily factor LIGHT (TNFSF14). Peripheral
blood, splenic, and tumor-infiltrating lymphocytes were isolated for phenotypic studies
and flow cytometry.
Results
Tumors exposed to a combination of LIGHT and IL-2 experienced a decrease in tumor
size compared with IL-2 alone that was not demonstrated in wild-type tumors or between
other treatment groups. Combination exposure also increased splenic central memory
CD8+ cells compared with IL-2 administration alone, while not increasing tumor-infiltrating
lymphocytes. In the periphery, the combination enhanced levels of circulating CD8
T-cells and central memory T-cells, while also increasing circulating T-regulatory
cells.
Conclusions
Combination of IL-2, whether soluble or liposomal, with exposure to LIGHT results
in increased CD8+ central memory cells in the spleen and periphery. New combination
immunotherapy strategies that support both effector and memory T-cell functions are
critical to enhancing durable antitumor responses and warrant further investigation.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Surgical ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer statistics, 2015.CA Cancer J Clin. 2015; 65: 5-29
- Vaccination with mitoxantrone-treated primary colon cancer cells enhances tumor-infiltrating lymphocytes and clinical responses in colorectal liver metastases.J Surg Res. 2019; 233: 57-64
- Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death.Cell Death Dis. 2017; 8: e2584
- Genetic evidence that intratumoral T-cell proliferation and activation are associated with recurrence and survival in patients with resected colorectal liver metastases.Cancer Immunol Res. 2015; 3: 380-388
- Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.Ann Surg Oncol. 2005; 12: 1005-1016
- Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012; 366: 2443-2454
- Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma.J Immunother. 2006; 29: 455-463
- PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520
- Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer.J Clin Oncol. 2010; 28: 3485-3490
- Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability.Immunity. 2016; 44: 698-711
- Systematic review of microsatellite instability and colorectal cancer prognosis.J Clin Oncol. 2005; 23: 609-618
- Precise identification of immunotherapeutic targets for solid malignancies using clues within the tumor microenvironment-Evidence to turn on the LIGHT.Oncoimmunology. 2016; 5: e1069937
- LIGHT elevation enhances immune eradication of colon cancer metastases.Cancer Res. 2017; 77: 1880-1891
- Shedding LIGHT (TNFSF14) on the tumor microenvironment of colorectal cancer liver metastases.J Transl Med. 2013; 11: 70
- Targeting tumors with LIGHT to generate metastasis-clearing immunity.Cytokine Growth Factor Rev. 2008; 19: 285-294
- Priming of naive T cells inside tumors leads to eradication of established tumors.Nat Immunol. 2004; 5: 141-149
- Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells.Proc Natl Acad Sci U S A. 2005; 102: 9571-9576
- Selective stimulation of T cell subsets with antibody-cytokine immune complexes.Science. 2006; 311: 1924-1927
- Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo.Nat Med. 2003; 9: 540-547
- The role of interleukin-2 in memory CD8 cell differentiation.Adv Exp Med Biol. 2010; 684: 28-41
- Interleukin-2-induced small unilamellar vesicle coalescence.Biochim Biophys Acta. 2001; 1514: 127-138
- Biopharmaceutics of liposomal interleukin 2, oncolipin.Cytokine. 2000; 12: 1691-1701
- In situ vaccination against a non-immunogenic tumour using intratumoural injections of liposomal interleukin 2.Cytokine. 2001; 16: 239-250
- Liposomal formulation of a self lymphoma antigen induces potent protective antitumor immunity.J Immunol. 1998; 160: 3637-3641
- Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma.BMC Genomics. 2014; 15: 190
- Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth.Nature. 2017; 552: 116-120
- Species-specificity of T cell stimulating activities of IL 2 and BSF-1 (IL 4): comparison of normal and recombinant, mouse and human IL 2 and BSF-1 (IL 4).J Immunol. 1987; 138: 1813-1816
- Utilization and impact of adjuvant chemotherapy among patients with resected stage II colon cancer: a multi-institutional analysis.J Surg Res. 2017; 215: 12-20
- Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer.Cancer. 2016; 122: 3277-3287
- Value in colorectal cancer TreatmentL where it is lacking, and why.Cancer J. 2016; 22: 232-235
- Impact of immunotherapy after resection of pancreatic cancer.J Am Coll Surg. 2019; 229: 19-27 e1
- Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.Science. 2006; 313: 1960-1964
- CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer.Cancer Res. 1998; 58: 3491-3494
- T cell death and memory.Science. 2001; 293: 245-248
- Immunological memory and protective immunity: understanding their relation.Science. 1996; 272: 54-60
- T cell memory.Annu Rev Immunol. 2002; 20: 551-579
- Inflaming the CD8+ T cell response.Immunity. 2006; 25: 19-29
- Dynamics of blood-borne CD8 memory T cell migration in vivo.Immunity. 2004; 20: 551-562
- Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.Nature. 1999; 401: 708-712
- Functionally heterogeneous CD8(+) T-cell memory is induced by Sendai virus infection of mice.J Virol. 1999; 73: 7278-7286
- Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.J Clin Invest. 2005; 115: 1616-1626
- Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation.Cell Mol Immunol. 2019; 16: 138-153
- PKC- is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells.Sci Rep. 2017; 7: 6594
- Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade.J Immunol. 2005; 175: 7746-7754
- Combining targeted immunotherapy with checkpoint blockade inhibits formation of colorectal liver metastases (abstract).Ann Surg Oncol. 2017; 24: 1-202
- Can colon cancer recurrence and metastases Be determined after surgical resection using a gene expression signature?.J Clin Oncol. 2017; 35: 1372-1373
- Gene-expression profiling to predict responsiveness to immunotherapy.Cancer Gene Ther. 2017; 24: 134-140
- The precursors of memory: models and controversies.Nat Rev Immunol. 2009; 9: 662-668
- Differential expansion of T central memory precursor and effector subsets is regulated by division speed.Nat Commun. 2020; 11: 113
- Clinical toxicity of interleukin-2.Drug Saf. 1992; 7: 417-433
- Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion.Cytotherapy. 2017; 19: 689-702
- Anti-cancer therapies employing IL-2 cytokine tumor targeting: contribution of innate, adaptive and immunosuppressive cells in the anti-tumor efficacy.Front Immunol. 2018; 9: 2905
Article info
Publication history
Published online: February 22, 2021
Accepted:
January 15,
2021
Received in revised form:
November 30,
2020
Received:
May 18,
2020
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
