Differentiation of circulating and tissue-resident memory CD8+ T cells infiltrating human renal cell carcinoma tumors 9357

Abstract Description Renal cell carcinoma (RCC) is a prevalent and deadly type of kidney cancer that responds to immune checkpoint blockade immunotherapy. However, tumor infiltration of CD8+ T cells has shown opposing effects on patient survival, which may be explained by functional heterogeneity among tumor-specific CD8+ T cells. In this study we observed that RCC tumors are infiltrated by circulating (Tcirc) and tissue-resident (Trm) memory CD8+ T cells that specifically recognize autologous RCC cells in a HLA class I-dependent manner. Trm cell populations displayed higher tumor reactivity than Tcirc cells. Trm cells exhibited reduced stemness potential and a higher exhausted state. In contrast, Tcirc cells showed a high stemness and cytotoxic potential. Single-cell transcriptomics revealed a rather heterogenous composition of memory populations, including cytotoxic and progenitor Tcirc subsets, as well as multiple Trm subsets, including exhausted Trm cells. TCR and trajectory analyses indicate that circulating progenitors lose their circulation and stemness potential in the tumor while progressively acquiring a tissue-resident differentiation program followed by a terminal differentiation state. Interestingly, tumor enrichment of Trm and cytotoxic Tcirc cells predicts better survival, while exhausted Trm and total CD8+ T cells predict worse survival. Our study delineates the differentiation pathway of tumor-specific memory CD8+ T cells infiltrating human renal cell carcinoma tumors Funding Sources This work was funded by Centro Científico y Tecnológico de Excelencia Ciencia & Vida FB210008 and FONDECYT grants 1212070 (A.L.), 11190897 (V.B.), 3220788 (S.H.), 3220741 (A.H.O.) and 3230650 (F.S.) from Agencia Nacional de Investigación y Desarrollo (ANID). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)