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Simple Summary: Not all cancer patients receiving immunotherapy by immune checkpoint blockade experience a clinical benefit. Our study was aimed at identifying biomarkers that could guide the selection of immunotherapy-responsive patients. Immunotherapy targets two major populations of lymphocytes: CD8 T cells, which directly kill tumor cells, and CD4 T cells, which provide help to CD8 T cells, the role of which in clinical responsiveness to immunotherapy has been less explored. We identified, in the blood of cancer patients, a population of CD4 T cells expressing inhibitory receptors targeted by immunotherapy. We showed that these cells were activated and proliferating, indicating their potential involvement in ongoing immune responses. Accordingly, we showed that they were specific for tumor antigens. In a prospective cohort, we showed that high proportions of these cells prior to therapy were associated with a response to immunotherapy. Tumor-infiltrating exhausted PD-1hiCD39+ tumor-antigen (Ag)-specific CD4 T cells contribute to the response to immune checkpoint blockade (ICB), but their circulating counterparts, which could represent accessible biomarkers, have not been assessed. Here, we analyzed circulating PD-1+CD39+ CD4 T cells and show that this population was present at higher proportions in cancer patients than in healthy individuals and was enriched in activated HLA-DR+ and ICOS+ and proliferating KI67+ cells, indicative of their involvement in ongoing immune responses. Among memory CD4 T cells, this population contained the lowest proportions of cells producing effector cytokines, suggesting they were exhausted. In patients with HPV-induced malignancies, the PD-1+CD39+ population contained high proportions of HPV Ag-specific T cells. In patients treated by ICB for HPV-induced tumors, the proportion of circulating PD-1+CD39+ CD4 T cells was predictive of the clinical response. Our results identify CD39 expression as a surrogate marker of circulating helper tumor-Ag-specific CD4 T cells. [ABSTRACT FROM AUTHOR]