Abstract 4782: Expression of programmed death-1 in CD8+ T cells from patients bearing PCA upon stimulation with common γ-chain cytokines

Abstract

Abstract Prostate cancer (PCA) is a leading cause of cancer death in men. Underlying immunosuppressive mechanisms in benign prostate hyperplasia (BPH) and PCA patients are not fully clarified. We analyzed homeostatic proliferation of CD8+ T cells upon stimulation with common receptor γ chain IL-2, IL-7 and IL-15 cytokines in PCA as compared to BPH patients. CD8+ T cells exhaustion was assessed by evaluating Programmed Death-1 (PD-1) receptor and its ligand PD-L1 expression in PBMC and tissue infiltrating CD8+ T cells from PCA and BPH patients. 57 BPH and 76 PCA patients were enrolled. Gene expression was quantified by Real-Time PCR. T cell proliferation was evaluated by CFSE dilution. CD132, CD122, PD-1 and PD-Ll expression were assessed by flow cytometry. IL-2, IL-7 and IL-15 gene expression were quantified in PCA (n=57) and BPH (n=32) tissues. IL-7 and IL-15 gene expression were significantly increased in PCA tissues as compared to BPH (p=0.024; p=0.031). No significant differences were observed for IL-2 gene expression. CD8+ cells from BPH (n=17) and PCA (n=21) patients showed a significantly decreased responsiveness to IL-7 and IL-15 (p=0.021; p=0.015) as compared to healthy donors (n=9). Response to IL-2 was similar. A trend towards a lower response to IL-15 in PCA as compared to BPH patients was detectable. Percentage of CD8+ T cells expressing the common γ chain (CD132) of homeostatic cytokines receptor is significantly decreased in PCA (n=13) and BPH (n=16) patients as compared to healthy donors (n=8) (p= 0.024; p<0.001). Percentage of CD8+ T cells expressing the common β chain (CD122) is significantly decreased in PCA patients as compared to healthy donors (p=0.035). No significant differences were noticed for the expression of the α chain of homeostatic cytokine receptor. Urged by these findings, we addressed the expression of PD-1 and its ligand in CD8+ T cells from BPH and PCA patients. In BPH (n=7) and PCA (n=7), %CD8+PD-1+ and %CD8+PD-L1+ T cells are increasing upon culture with homeostatic cytokines. In freshly isolated CD8+ cells, a highly significant increase in the %CD8+PD-1+ cells was observed in PCA (n=32) and BPH (n=22) as compared to healthy donors (p<0.001; p<0.001). In contrast, PD-L1 expression in CD8+ cells was similar in BPH and PCA patients and in healthy donors. A large majority of CD8+ cells infiltrating BPH or PCA tissues (83±22% for BPH, n=9; 88±17% for PCA, n=7) were PD-1+, whereas PD-L1 was expressed in 51±43% and 37±39% of infiltrating CD8+ T cells in BPH and PCA, respectively. Taken together these data indicate that both BPH and PCA patients display a decreased responsiveness to IL-7 and IL-15 homeostatic cytokines. Interestingly, high percentages of peripheral blood CD8+ T cells express PD-1 in BPH and PCA patients. Notably, PD-1 and its ligand are highly expressed in tissue infiltrating CD8+ T cells in BPH and PCA patients, thus raising the issue of the role of T cells exhaustion in PCA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4782.