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Circulating Exhausted PD-1+CD39+ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1 Axis Blockade. 2022

Carlos Martinez-Gomez, and Marie Michelas, and Clara-Maria Scarlata, and Anna Salvioni, and Carlos Gomez-Roca, and Victor Sarradin, and Françoise Lauzéral-Vizcaino, and Virginie Féliu, and Agnès Dupret-Bories, and Gwénaël Ferron, and Jérôme Sarini, and Christel Devaud, and Jean-Pierre Delord, and Camille-Charlotte Balança, and Alejandra Martinez, and Maha Ayyoub

Centre de Recherches en Cancérologie de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Université de Toulouse, 31037 Toulouse, France.

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.