CD4 + follicular helper-like T cells are key players in anti-tumor immunity

To determine the nature of CD4 T cells that provide ‘help’ for generating robust anti-tumor CD8 cytotoxic T cell (CTL) responses, we profiled the transcriptomes of patient-matched CD4 and CD8 T cells present in the tumor micro-environment (TME) and analyzed them jointly using integrated weighted gene correlation network analysis. We found the follicular helper T cell (T) program in CD4 T cells was strongly associated with proliferation and tissue-residency in CD8 CTLs. Single-cell analysis demonstrated the presence of T-like cells and features linked to cytotoxic function and their provision of CD8 T cell ‘help’. Tumor-infiltrating T-like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy. Adoptive transfer or induction of T cells in mouse models resulted in augmented CD8 CTL responses and impairment of tumor growth, indicating an important role of T-like CD4 T cells in anti-tumor immunity.