Abstract
CD4+ Tcells 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 Tcell receptor sequences to identify signatures and functional correlates of tumor-specific CD4+ Tcells infiltrating human melanoma. Conventional CD4+ Tcells 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+ Tcells in the tumor correlated with the transcriptional states of CD8+ Tcells 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+ Tcells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.
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