Veatch et al. investigated CD4+ T cell phenotypes and functions in human melanoma. Using scRNAseq and TCR sequencing, 350 neoantigen- and tumor antigen-specific CD4+ T cells, obtained from primary tumors of four patients with melanoma, were found to express CXCL13 and PD-1, and could be subdivided into distinct functional clusters: a proliferative cluster, a Tfh-like subset colocalizing with B cells in the TME, and a cytolytic subset expressing Tim3 and IFNγ. The presence of CXCL13+ CD4+ T cells correlated with overall survival and local macrophage, CD8+ T, and B cell activation, suggesting CD4+ T cells have key and diverse beneficial roles in the TME.
Contributed by Katherine Turner
ABSTRACT: 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.