Neoantigen-specific CD4 T cells in human melanoma have diverse differentiation states and correlate with CD8 T cell, macrophage, and B cell function.

CD4 T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4 T cells infiltrating human melanoma. Conventional CD4 T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13 CD4 T cells in the tumor correlated with the transcriptional states of CD8 T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor-specific CD4 T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.