Decline of programmed death-1-positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade

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

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

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

Results: 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 with patients who did not show a significant decline of PD-1⁺ Tregs after the first treatment, those who did had better clinical outcomes 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 of more favourable 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% confidence interval 0·0042-0·97).

Conclusions: 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. 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. What's already known about this topic? Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1⁺ T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD-1⁺ Tregs appear to have better clinical outcome under PD-1 treatment.