Impaired Natural Killer Cell Lysis in Breast Cancer Patients with High Levels of Psychological Stress is Associated with Altered Expression of Killer Immunoglobin-Like Receptors

Varker, Kimberly A.; Terrell, Catherine E.; Welt, Marilyn; Suleiman, Samer; Thornton, Lisa; Andersen, Barbara L.; Carson, William E.

doi:10.1016/j.jss.2006.08.037

« Previous Next »Journal of Surgical Research
Volume 139, Issue 1 , Pages 36-44, 1 May 2007

Impaired Natural Killer Cell Lysis in Breast Cancer Patients with High Levels of Psychological Stress is Associated with Altered Expression of Killer Immunoglobin-Like Receptors

Kimberly A. Varker, M.D.
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
Catherine E. Terrell, B.S.
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Psychology, The Ohio State University, Columbus, Ohio
Marilyn Welt, B.S.
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Psychology, The Ohio State University, Columbus, Ohio
Samer Suleiman, B.S.
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Psychology, The Ohio State University, Columbus, Ohio
Lisa Thornton, Ph.D.
- Department of Psychology, The Ohio State University, Columbus, Ohio
Barbara L. Andersen, Ph.D.
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Psychology, The Ohio State University, Columbus, Ohio
- Institute of Behavioral Medical Research, The Ohio State University, Columbus, Ohio
William E. Carson III, M.D.
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- College of Medicine, The Ohio State University, Columbus, Ohio
- Department of Surgery, The Ohio State University, Columbus, Ohio
- To whom correspondence and reprint requests should be addressed at Division of Surgical Oncology, The Ohio State University, N924 Doan Hall, 410 W. 10th Avenue, Columbus, OH 43210.

Received 18 April 2006 published online 10 February 2007.

Background

We previously reported that cancer-related psychological stress is associated with reduced natural killer (NK) cell lysis. We hypothesized that reduced NK cell cytotoxicity in patients with increased levels of stress would correlate with alterations in the expression of inhibitory NK cell receptors (killer immunoglobulin-like receptors, or KIRs). The specific aim of this study was to examine KIR expression in patients with high or low levels of psychologic stress and correlate alterations in KIR expression with NK cell function.

Materials and Methods

Two hundred twenty-seven patients underwent baseline evaluation of cancer-related psychological stress and were randomized to psychosocial intervention versus observation. From this population, two groups were defined based on pretreatment measurements of NK lytic activity, stress levels, and the availability of cryopreserved peripheral blood mononuclear cells (PBMC). Group I (n = 9) had low stress by the Impact of Events Scale (IES), and high NK cell lysis at the 50:1 effector: target ratio (NK₅₀ = 52–89%). Group II (n = 8) had high stress and low NK₅₀ (27–52%). Lymphokine activated killer (LAK) activity, antibody dependent cellular cytotoxicity (ADCC), and expression of cytokine receptors, adhesion molecules, and killer immunoglobulin-like receptors (KIRs) were assessed in PBMC.

Results

Incubation of PBMC with NK-stimulatory cytokines (IL-2, IL-12, or IL-15) led to significant increases in cytotoxic activity regardless of IES/NK₅₀ scores. There were no significant group differences in NK cell surface expression of the IL-2 receptor components CD25 and CD122, antibody-dependent lysis of HER2/neu-positive SKBr3 cells treated with an anti-HER2/neu monoclonal antibody, expression of adhesion molecules (CD2, CD11a, CD18) and markers of activation (CD69), or expression of the KIRs CD158a, NKG2a, NKB1, and CD161. However, levels of CD158b were significantly higher in Group I after incubation in media alone or with IL-2, and CD94 expression was significantly lower in Group I after incubation with IL-2.

Conclusions

In this study of a small subset of breast cancer patients chosen from a previous clinical trial of psychosocial intervention for breast cancer, impaired NK lysis in breast cancer patients with high levels of psychological stress was associated with alterations in surface expression of killer immunoglobulin-like receptors. However, immune effectors retained the ability to lyse antibody-coated targets and to initiate lymphokine-activated killer activity, irrespective of stress levels or baseline NK₅₀.

Key Words: breast cancer, killer immunoglobulin-like receptors (KIR), natural killer (NK) cells, psychologic stress