PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

Abstract

a E (CD103)b 7 is a TGFb-regulated integrin that mediates retention of lymphocytes in peripheral tissues by binding to E-cadherin expressed on epithelial cells. We recently reported that a E (CD103)b 7 specifically demarcates intraepithelial CD8 þ tumor-infiltrating lymphocytes (CD8 TIL) in ovarian cancer and that CD103 þ TIL have a surface profile consistent with an active effector phenotype (HLA-DR þ , Ki67 þ , and CD127 lo ). These findings led us to hypothesize that, over time, CD103-mediated retention of CD8 TIL within the tumor epithelium might result in chronic stimulation by tumor antigen, which in turn might lead to an exhausted phenotype. To investigate this possibility, we evaluated PD-1 expression in a large cohort of ovarian tumors (N ¼ 489) with known CD103 þ TIL content. PD-1 þ cells were present in 38.5% of high-grade serous carcinomas (HGSC), but were less prevalent in other histologic subtypes. PD-1 þ TIL were strongly associated with increased disease-specific survival in HGSC (HR, 0.4864; P ¼ 0.0007). Multicolor immunohistochemistry and flow cytometry revealed a high degree of PD-1 and CD103 coexpression, specifically within the CD8 TIL compartment. PD-1 þ CD103 þ CD8 TIL were quiescent when assessed directly ex vivo yet were capable of robust cytokine production after pharmacologic stimulation. Moreover, they showed negligible expression of additional exhaustion-associated markers, including TIM-3, CTLA-4, and LAG-3. Thus, as hypothesized, CD103 þ CD8 TIL express PD-1 and appear quiescent in the tumor microenvironment. However, these cells retain functional competence and demonstrate strong prognostic significance. We speculate that, after standard treatment, PD-1 þ CD103 þ CD8 TIL might regain functional antitumor activity, an effect that potentially could be augmented by immune modulation. Cancer Immunol Res; 3(8); 926-35. Ó2015 AACR.

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

“…The protective effect of T RM cells in cancer is linked to their high degree of cytotoxicity, which is correlated with the magnitude of their perforin and granzyme expression [14]. In spite of expressing cytotoxic mediators, T RM cells in the tumour express the exhaustion markers PD‐1, T cell immunoglobulin and mucin domain 3 (TIM‐3) and lymphocyte‐activation gene 3 (LAG‐3) [34]. In accordance with these previous findings, in this study we have demonstrated a high number of PD‐1 + T RM cells from the tumour (Fig.…”

Combined Immunoscore of CD103 and CD3 Identifies Long-Term Survivors in High-Grade Serous Ovarian Cancer

“…In our series, intraepithelial CD103 alone was superior to CD8 and CD3 (low cutoff at 91/HPF) confirming recently published data. 5,7,25 In addition, high intraepithelial CD3 + lymphocytes with an optimized cutoff with 7 lymphocytes/ HPF identified a group of long-term survivors with 90% 5-year survival in optimally resected and platin-sensitive patients. This finding confirms the study of Gooden et al, 26 who showed in a meta-analysis of 52 studies, that CD3 + TIL showed a stronger prognostic effect than CD8-positive TIL.…”

Targeting the programmed cell death-1 pathway in breast and ovarian cancer

“…A retrospective analysis of archived ovarian tumors demonstrated a higher rate of 5-year overall survival in TIL positive tumors (38.0%) relative to TIL negative tumors (4.5%) (P < 0.001) [28]. Additional studies have shown that high levels of PD-1/PD-L1 expression by tumor cells [29] or by TILs [29,30] are associated with favorable prognosis in high-grade serous ovarian cancer patients. Conversely, another study showed a significant inverse correlation between the intraepithelial CD8 þ T-cell count and PD-L1 expression by ovarian tumors, with a 5-year survival of 86.2% for ovarian cancer patients with PD-L1 low tumors compared with 59.2% for those with PD-L1 high tumors (P ¼ 0.040) [31].…”