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 in vitro 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 CD39⁺CD69⁺ 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, in vitro activated CD4⁺ T cells developed into cytotoxic CD4^- T cells in vivo 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.