Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells

Cytotoxic CD8 T cells are the main focus of efforts to understand anti-tumor immunity and immunotherapy. The adoptive transfer of tumor-reactive cytotoxic CD8 T lymphocytes expanded and differentiated has long been considered the primary strategy in adaptive anti-tumor immunity, however, the majority of the transferred tumor antigen-specific CD8 T cells differentiated into CD39CD69 exhausted progenies, limiting its effects in repressing tumor growth. Contrarily, less attention has been addressed to the role of CD4 T cells during tumorigenesis. Using a mouse model of metastatic melanoma, we found that transferring tumor-specific CD4 T cells into recipients induces substantial regression of the established metastatic tumors. Notably, activated CD4 T cells developed into cytotoxic CD4 T cells and get exhausted gradually. The blockade of PD-L1 signaling resulted in an expansion of tumor specific CD4 T cells, which could better control the established metastatic melanoma. Moreover, the tumor-specific memory CD4 T cell can prevent mice from tumor metastasis, and the tumor-specific effector CD4 T cells can also mitigate the established metastatic tumor. Overall, our findings suggest a novel mechanism of CD4 T cells in curtailing tumor metastasis and confirm their therapeutic role in combination with PD-L1 blockade in cancer immunotherapy. Hence, a better understanding of cytotoxic CD4 T cell-mediated tumor regression could provide an alternative choice for patients exhibiting suboptimal or no response to CD8 T cell-based immunotherapies.