Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression

Abstract

The efficacy of immunotherapy in cancer patients is influenced by differences in their immune status. An evaluation of immunocompetence before therapy may help to predict therapeutic success and guide the selection of appropriate regimens. We assessed the preexisting cellular immunity against prostate-specific antigen (PSA) in untreated prostate cancer patients and healthy controls through measurement of the phenotype and function of CD8(+) T cells. Our data show that the majority of healthy men possess functional PSA-specific CD8(+) T cells in contrast to cancer patients, where <50 % showed a CD8(+) T cell response. PSA146-154-specific CD8(+) T cells of these patients had a higher expression of the activation marker CD38 and the exhaustion marker Tim-3, indicating that PSA-specific cells are exhausted. The heterogeneity of the CD8(+) T cell response against PSA in prostate cancer patients may influence their response to therapy and is a factor to be taken into account while designing and selecting treatment regimens.

Tim‐3 and its role in regulating anti‐tumor immunity

“…It has been well‐documented that the protein and/or mRNA expression of Tim‐3 is significantly up‐regulated in tumor tissue samples and is associated with poor prognosis of patients with prostate cancer, ccRCC, colon cancer, bladder urothelial carcinoma, cervical cancer, and gastric cancer . The increased Tim‐3 expression on tumor antigen‐specific CD8 + T cells is also correlated with dysfunction of CD8 + T cell and poor prognosis in HBV‐associated hepatocellular carcinoma and prostate cancer patients . Similarly, increased Tim‐3 expression on NK cells from patients with gastric cancer is associated with tumor progression .…”

TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

“…In addition, among CD4 + TIL, TIM-3 is preferentially expressed on Foxp3 + CD4 + Treg cells, and the frequency of CD4 + TIM-3 + TIL is correlated with poor patient survival [54]. TIM-3 was also shown to be expressed in TIL or tumor antigen-specific T cells in peripheral blood from many cancer types such as hepatocellular cancer, cervical cancer, colorectal cancer, ovarian cancer [55], NSCLC [56,57], head and neck cancer [58], renal cell carcinoma (RCC) [59], gastric cancer [60], esophageal cancer [61], prostate cancer [62], and non-Hodgkin lymphoma [63]. …”

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

“…Tumor-infiltrating CD4 and CD8 cells co-express TIM-3 and PD-1 in murine models of colon adenocarcinoma, melanoma and mammary adenocarcinoma (Assal et al 2015). In humans, TIM-3 is expressed on tumorinfiltrating lymphocytes or T cells in the peripheral blood of patients with various types of cancer such as hepatocellular cancer, cervical cancer, colorectal cancer, ovarian cancer, non-small-cell lung cancer, head and neck cancer, renal cell carcinoma, gastric cancer, esophageal cancer, prostate cancer and non-Hodgkin lymphoma (Yang et al 2012, Jie et al 2013, Yan et al 2013, Japp et al 2015, Thommen et al 2015, Cai et al 2016, Xie et al 2016. Preclinical models show conflicting results for the administration of TIM-3-targeting monoclonal antibody.…”