Tumor-specific but immunosuppressive CD39+CD8+ T cells exhibit double-faceted roles in clear cell renal cell carcinoma

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Authors: Yong Joon Lee ; Seung Hyuck Jeon ; Jin Hee Yeo ; Sun-Ju Byeon ; Jae Hyung Jung ; Heejin Nam ; Minwoo Jeon ; Eui-Soon Kim ; Jeon Yeob Jang ; Chul-Ho Kim ; Kee Yang Chung ; Jung Yun Lee ; Shin Hwang ; Jee Ye Kim ; Seung-Il Kim ; Jae-Ho Cheong ; Chang Gon Kim ; Sang Joon Shin ; Su-Hyung Park ; Minsun Jung ; Minyong Kang ; Seong Il Seo ; Eui-Cheol Shin

MeSH: Animals ; Antigens, CD* / metabolism ; Apyrase* / immunology ; Apyrase* / metabolism ; CD8-Positive T-Lymphocytes* / immunology ; CD8-Positive T-Lymphocytes* / metabolism ; Carcinoma, Renal Cell* / genetics ; Carcinoma, Renal Cell* / immunology ; Carcinoma, Renal Cell* / pathology ; Female ; Humans ; Kidney Neoplasms* / genetics ; Kidney Neoplasms* / immunology ; Kidney Neoplasms* / pathology ; Lymphocytes, Tumor-Infiltrating / immunology ; Lymphocytes, Tumor-Infiltrating / metabolism ; Male ; Prognosis ; Receptors, Antigen, T-Cell / metabolism ; Von Hippel-Lindau Tumor Suppressor Protein / genetics

Keywords: CD39(+)CD8(+) T cells ; adenosine pathway ; anti-PD-1 therapy ; clear cell renal cell carcinoma ; hypoxia ; immunosuppressive activity ; paradoxical prognosis ; tumor antigen specificity ; tumor microenvironment

Abstract: CD39+CD8+ T cells are known as tumor-antigen-specific cells among CD8+ tumor-infiltrating lymphocytes (TILs). However, CD39+CD8+ T cells also reportedly exhibit immunosuppressive activity in hypoxic tumor models. Here, we investigate CD39+CD8+ TILs in clear cell renal cell carcinoma (ccRCC), a Von Hippel-Lindau (VHL) mutation-associated hypoxic tumor. Single-cell analyses confirm that CD39+CD8+ cells are a terminally exhausted subset of tumor-specific CD8+ TILs. CD39+CD8+ T cell development is directly induced by cAMP and T cell receptor (TCR) signaling. Analysis of a renal cell carcinoma (RCC) cohort reveals that the proportion of CD39+CD8+ TILs is associated with a high tumor mutational burden and hypoxic features. Ex vivo functional assays reveal that CD39+CD8+ TILs exert immunosuppressive activity via ectonucleotidase activity- and adenosine-dependent mechanisms. CD39+CD8+ TIL enrichment predicts poor prognosis in patients with ccRCC yet also predicts favorable treatment responses to anti-programmed cell death protein 1 (PD-1) therapy. This paradoxical prognostic significance in ccRCC is explained by the dual properties of CD39+CD8+ TILs: tumor antigen specificity and immunosuppressive activity.