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

作者：Liu, Qiao^*; Wang, Lisha; Lin, Huayu; Wang, Zhiming; Wu, Jialin; Guo, Junyi; Wen, Shuqiong; Ran, Ling; Yue, Zhengliang; Su, Xingxing; Wu, Qing; Tang, Jianfang; Li, Zhirong; Hu, Li; Xu, Lifan; Ye, Lilin^*; Huang, Qizhao^*

来源：Frontiers in Immunology, 2022, 13: 875718.

DOI：10.3389/fimmu.2022.875718

• tumor specific
• CD4(+)T cells
• CD4(-)T cells
• metastasis
• melanoma

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.

• 单位
  中山大学; 南方医科大学