CD39+CD8+ T cells exhibit a distinct phenotype among tumor-infiltrating tumor-antigenspecific CD8+ T cells

Abstract

Abstract Recent studies have spotlighted CD39 expression on tumor-infiltrating CD8+ T cells as an exhaustion marker (Cancer Research 2018, 1:78) and tumor antigen reactivity (Nature Communications 2018, 9:1). In the present study, we examined characteristics of CD39+CD8+ T cells among tumor-infiltrating lymphocytes (TILs) obtained from various types of tumors, including ovarian cancer, stomach cancer and hepatocellular carcinoma, to gain better understanding of CD39 expression on CD8+ T cells. To identify tumor antigen-specific CD8+ T cells, we used 11 HLA-A*A201 multimers specific for tumor associated antigens, including MAGE A1, NY-ESO-1, and AFP. CD39 expression of tumor antigen-specific CD8+ T cells was significantly higher in TILs than in peripheral blood lymphocytes. However, all of tumor-infiltrating tumor antigen-specific CD8+ T cells did not express CD39. As known previously (Nature 2018, 557:7706), tumor-infiltrating bystander CD8+ T cells, specific to viral epitopes, lack CD39 expression. Among tumor-infiltrating tumor antigen-specific CD8+ T cells, CD39+CD8+ T cells exhibited more severely exhausted features than CD39−CD8+ T cells. For example, the percentage of multiple immune checkpoint receptors-expressing cells was significantly higher in CD39+CD8+ T cells compared to CD39−CD8+ T cells. Moreover, higher proportion of T-betlow/Eomeshighcells and and lower expression of CD127 were observed in CD39+CD8+ T cells. In addition, CD39+CD8+ T cells expressed higher levels of tissue residency markers, such as CD103 and CD69. In conclusion, CD39+CD8+ T cells exhibit distinct phenotypes that represent severe exhaustion and terminal differentiation among tumor-infiltrating tumor-antigen-specific CD8+ T cells.