| Summary: | Tumor-infiltrating exhausted PD-1<sup>hi</sup>CD39<sup>+</sup> 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<sup>+</sup>CD39<sup>+</sup> 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<sup>+</sup> and ICOS<sup>+</sup> and proliferating KI67<sup>+</sup> 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<sup>+</sup>CD39<sup>+</sup> 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<sup>+</sup>CD39<sup>+</sup> 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.
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