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Purpose:
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Tumor-specific T cells likely underpin effective immune checkpoint-blockade therapies. Yet, most studies focus on Treg cells and CD8+ tumor-infiltrating lymphocytes (TILs). Here we study CD4+ TILs in human lung and colorectal cancers and observe that non-Treg CD4+ TILs average more than 70% of total CD4+ TILs in both cancer types. Leveraging high dimensional analyses including mass cytometry, we reveal that CD4+ TILs are phenotypically heterogeneous, within each tumor and across patients. Consistently, we find different subsets of CD4+ TILs showing characteristics of effectors, tissue resident memory (Trm) or exhausted cells (expressing PD-1, CTLA-4 and CD39). In both cancer types, the frequencies of CD39? non-Treg CD4+ TILs strongly correlate with frequencies of CD39? CD8+ TILs, which we and others have previously shown to be enriched for cells specific for cancer-unrelated antigens (bystanders). Ex-vivo, we demonstrate that CD39? CD4+ TILs can be specific for cancer unrelated antigens, such as HCMV epitopes. |
