CD39 identifies the CD4+ tumor-specific T cell population in human cancer.

The accumulation of tumor-specific CD4+ and CD8+ effector T cells is key to an effective antitumor response. Locally, CD4+ T cells promote the recruitment and effector function of tumor-specific CD8+ T cells and activate innate killer cells in the tumor. Here, we showed that tumor-specific CD4+ T cells were predominantly present in the CD39+ subset of tumor-infiltrating lymphocytes (TIL). The CD39+ CD4+ and CD8+ TIL were detected in 3 different tumor types, and displayed an activated (PD-1+, HLA-DR+) effector memory phenotype. CD4+CD39+ single cell RNA sequenced TIL shared similar well-known activation, tissue residency, and effector cell-associated genes with CD8+CD39+CD103+ TIL. Finally, analysis of directly ex-vivo cell sorted and in vitro expanded pure populations of CD39-positive and negative CD4+ and CD8+ TIL revealed that tumor-specific antigen reactivity was almost exclusively detected among CD39+ cells.