The ability of CD8⁺ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8⁺ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39^highCD8⁺ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8⁺ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39⁺CD8⁺ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39⁺CD8⁺ T cells inhibited IFNγ production by responder CD8⁺ T cells. In specimens from breast cancer and melanoma patients, CD39⁺CD8⁺ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induce CD39 on human CD8⁺ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8⁺ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8⁺ T cells, with implications for defining a biomarker of T-cell dysfunction and a target for immunotherapeutic intervention.Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8⁺ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function. Cancer Res; 78(1); 115-28. ©2017 AACR.

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