Tissue-Resident Memory CD4⁺ T Cells Play a Dominant Role in the Initiation of Antitumor Immunity

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 mouse model, the mice of which are deficient in the TCRα repertoire, specifically lacking invariant NKT and mucosal-associated invariant T cells, we found that the deficiency in TCRα repertoire diversity did not affect the antitumor immunity, at least to B16BL6 melanoma and EO771 breast cancer. However, after acquiring thymocytes or splenocytes from wild-type mice, these knockout mice exhibited greatly enhanced and long-lasting antitumor immunity. This enhanced antitumor immunity depended on CD4⁺ T cells, especially CD4⁺ tissue-resident memory T (T_RM) cells, but not invariant NKT or CD8⁺ T cells. We also present evidence that CD4⁺ T_RM cells initiate antitumor immunity through IFN-γ, and the process is dependent on NK cells. The CD4⁺ T_RM/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⁺ T_RM cells play a dominant role in the initiation of antitumor immunity.