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

      1 , 2 , 3
      Cancer immunology research

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          Abstract

          αE(CD103)β7 is a TGFβ-regulated integrin that mediates retention of lymphocytes in peripheral tissues by binding to E-cadherin expressed on epithelial cells. We recently reported that αE(CD103)β7 specifically demarcates intraepithelial CD8(+) tumor-infiltrating lymphocytes (CD8 TIL) in ovarian cancer and that CD103(+) TIL have a surface profile consistent with an active effector phenotype (HLA-DR(+), Ki67(+), 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 = 489) with known CD103(+) TIL content. PD-1(+) cells were present in 38.5% of high-grade serous carcinomas (HGSC), but were less prevalent in other histologic subtypes. PD-1(+) TIL were strongly associated with increased disease-specific survival in HGSC (HR, 0.4864; P = 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(+)CD103(+) 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(+) 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(+)CD103(+) CD8 TIL might regain functional antitumor activity, an effect that potentially could be augmented by immune modulation.

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          Author and article information

          Journal
          Cancer Immunol Res
          Cancer immunology research
          2326-6074
          2326-6066
          Aug 2015
          : 3
          : 8
          Affiliations
          [1 ] Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada. jwebb@bccrc.ca.
          [2 ] Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
          [3 ] Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
          Article
          2326-6066.CIR-14-0239
          10.1158/2326-6066.CIR-14-0239
          25957117
          4eefed77-4f61-4bcb-bfb1-c3d9757f59e9
          ©2015 American Association for Cancer Research.
          History

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