Circulating Exhausted PD-1⁺CD39⁺ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1...

Tumor-infiltrating exhausted PD-1^hiCD39⁺ 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.