PD-1 and ICOS co-expression identifies tumor-reactive CD4 Th cells in human solid tumors

Abstract CD4 T helper (Th) cells play a key role in orchestrating immune responses, but the identity of the CD4 Th cells involved in the immune response against cancer remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and microsatellite stable colorectal cancers and identified a subset of CD4 Th cells distinct from FOXP3+ regulatory T cells that co-express PD-1 and ICOS. This cell population, which was present in the tumor but absent in the periphery, features of chronic stimulation and displays characteristics of tissue-resident memory T cells. PD-1+ICOS+ tumor-infiltrating (TIL) CD4 Th cells are located primarily in the tumor stroma in proximity to MHC class II+ cells and are proliferating, suggesting local antigen recognition. The T-cell receptor repertoire of the PD-1+ICOS+ CD4 Th TIL is oligoclonal, with T-cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4 Th TIL were shown to recognize both tumor-associated antigens and tumor-specific neoantigens, which were distinct from the epitopes recognized by the CD8 T cells from the same patients. Our findings provide an approach for isolating tumor-reactive CD4 Th TIL directly ex vivo and imply that harnessing the cooperation between CD4 and CD8 T cells might lead to more efficient tumor recognition and control in cancer patients. Supported by the Providence Portland Medical Foundation and the Developmental Research Program for Head and Neck Cancer.