The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in context to programmed death 1 (PD-1) blockade is not completely understood.

To assess the impact of PD-1 blocking antibody treatment on Treg-subpopulations in the blood.

We studied circulating Treg-subpopulations in melanoma patients under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcome.

These analyses revealed that the frequency of CD4+CD25++CD127-PD-1+ lymphocytes (PD-1+ Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8·6%, P = 0·043]. Compared to patients who did not show a significant decline of PD-1+ Tregs after the first treatment, those who did, had better clinical outcome with respect to progression-free survival (PFS; P = 0·022) and melanoma-specific death (MSD, P = 0·0038). Multivariate analysis confirmed that a significant decline of PD-1+ Tregs in peripheral blood after the first treatment cycle is a significant predictor for more favorable PFS and MSD (P = 0·04 and 0·017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0·047; odds ratio: 0·064; 95% CI: 0·0042 to 0·97).

We provide preliminary evidence that circulating PD-1+ Tregs rapidly decline after the initiation of treatment with PD-1 blocking antibodies which is associated with reduced risk of melanoma progression and MSD. In patients showing no decrease of these PD-1+ Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. This article is protected by copyright. All rights reserved.