Tissue-resident memory CD4+ T cells play a dominant role in the initiation of antitumor immunity

Abstract Tumor immunology has been studied extensively. Tumor immunology-based cancer immunotherapy has become one of the most promising approaches for cancer treatment. However, one of the fundamental aspects of tumor immunology – the initiation of antitumor immunity – is not fully understood. Compared to that of CD8+ T cells, the effect of CD4+ T cells on antitumor immunity has not been fully appreciated. Using a gene knockout (KO) mouse model – these mice are deficient in TCRa repertoire, specifically lacking iNKT and MAIT cells - we found that the deficiency in TCRa repertoire diversity did not affect the antitumor immunity, at least to melanoma and breast cancer. However, after acquiring thymocytes or splenocytes from wild-type mice, these KO mice exhibited greatly enhanced and long-lasting antitumor immunity. This enhanced antitumor immunity depended on CD4+ T cells, especially tissue-resident memory (TRM) CD4+ T cells, but not iNKT or CD8+ T cells. We also present evidence that CD4+ TRM cells initiate antitumor immunity through IFN-g, and the process is dependent on NK cells but not macrophages. The CD4+ TRM/NK axis appears to control tumor formation and development by eliminating tumor cells and modulating the tumor microenvironment. Taken together, our results demonstrated that CD4+ TRM cells play a dominant role in the initiation of antitumor immunity. Supported by Washington State University Start-up funds