• [Cell Reports Medicine] Tumor-specific but immunosuppressive CD39+CD8+ T cells exhibit double-faceted roles in clear cell renal
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  • 2025-12-22 09:55:18|
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[Title]
Tumor-specific but immunosuppressive CD39+CD8+ T cells exhibit double-faceted roles in clear cell renal cell carcinoma

[Corresponding Author]
 * Eui-Cheol Shin(ecshin@kaist.ac.kr)
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
 * Minsun Jung(jjunglammy@yuhs.ac)
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea

[Journal] 
Cell Reports Medicine, Volume 6, Issue 10, 21 October 2025, 102360
https://doi.org/10.1016/j.xcrm.2025.102360

[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. 

 
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