Abstract 3658: The expression of genes encoding common gamma-chain cytokines is associated with tissue infiltration by CD8+ T cells displaying an “exhausted” phenotype in benign prostatic hyperplasia and prostate cancer
Authors: Mengus Chantal , Magnen Clémentine Le , Bubendorf Lukas , Bachmann Alexander , Heberer Michael , Spagnoli Giulio C. , Wyler Stephen 
Published: June 2012

Objectives: Prostate cancer (PCA) is a leading cause of cancer related-death in men. Immunotherapy may provide alternative therapy for patients with castration-resistant PCA. Immunosuppressive mechanisms in benign prostatic hyperplasia (BPH) and PCA patients are not fully clarified. We analyzed homeostatic cytokines gene expression in tissue from patients bearing either PCA or BPH. CD8+ T cells exhaustion was assessed by evaluating Programmed Death-1 (PD-1) and its ligand PD-L1 expression in freshly isolated tissue infiltrating and peripheral blood CD8+ T cells.

Methods: 78 BPH, 93 PCA patients were enrolled. Gene expression was evaluated by Real-Time-PCR. Protein expressions were assessed by flow cytometry.

Results: IL-6, IL-7 and IL-15 gene expression were significantly increased in PCA tissues as compared to BPH (p=0.0077; p=0.0244 and p=0.0316, respectively). No significant differences were observed in IL-2, IL-17 and IL-21 gene expression.

A majority of CD8+ T cells infiltrating BPH or PCA tissues were PD-1+ (82.78±7.33% and 87.63±6.41%, respectively), whereas PD-L1 was expressed in 50.71±14.42% and 36.97±14.95% of tissue infiltrating CD8+ T cells in BPH and PCA, respectively. PD-L2 was expressed in 10.15±5.97% and 13.70±7.66% of tissue infiltrating CD8+ T cells in BPH and PCA, respectively.

In peripheral blood CD8+ T cells, PD-1, -L1 and -L2 expressions were similar in BPH (26.36±2.81%, 23.74±4.78% and 1.41±0.26%; respectively) and PCA patients (26.29±2.80, 26.56±3.23 and 4.40±1.84; respectively). CD8+PD-1+ cells were in majority effector memory and effector cells in both groups, while CD8+PD-L1+ cells were mainly effector and naïve cells.

In peripheral blood CD8+ T cells from BPH and PCA patients, %CD8+PD-L1+ cells was correlating with %CD8+CD25+ cells (p=0.011 and r=0.790, p=0.044 and r=0.646; respectively).

Percentages of CD8+PD-1+ cells from patients bearing either BPH or PCA were significantly increasing upon culture with IL-7 and IL-15. In addition, the basal level of Stat5 phosphorylation in peripheral blood CD8+ T cells from PCA patients was significantly higher as compared to BPH (p=0.045), and Stat5 activation was similarly increased upon culture with homeostatic cytokines in the both groups.

Conclusion: We demonstrated that tissues from patients bearing BPH and PCA are expressing inflammatory homeostatic cytokine genes. Percentages of tissue infiltrating and peripheral blood CD8+ T cells from both groups expressing PD-1 and ligands are high. In addition, homeostatic cytokines are able to up-regulate in vitro expression of these exhaustion molecules in peripheral blood CD8+ T cells from patients bearing either BPH or PCA.

Cytokine rich tumour environment might lead to T cell exhaustion rather than activation, thus raising the issue of the role of T cells exhaustion in PCA.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2011-3658