A Brief Communication on Circulating PD-1-positive T-Regulatory Lymphocytes in Melanoma Patients Undergoing Adjuvant Immunotherapy With Nivolumab

Abstract

Upregulation of T-regulatory lymphocytes (Tregs) is one of numerous immune escape mechanisms of malignancies. In the present pilot study we aimed to study the effect of adjuvant nivolumab during the initiation of treatment on circulating Tregs subpopulations in patients with stage III melanoma. We subsequently recruited patients with stage III melanoma who had the indication for adjuvant anti-programmed death 1 (PD-1) treatment with nivolumab. Blood collections were performed before the initiation of nivolumab and before every 2-week therapy cycle. Flow cytometry was performed for the determination of circulating CD4CD25highCD127PD-1(PD-1Tregs) and CD4CD25highCD127CTLA-4 (CTLA-4Tregs) Treg populations. Circulating PD-1Tregs [18.1% (range, 2.9%-41.7%) vs. 4.2% (0.4%-9.8%), P=0.0001] significantly decreased after the first cycle of immunotherapy and maintained decreased during a 3-month course of treatment. By contrast, CTLA-4Tregs significantly increased after the first nivolumab dose when compared with CTLA-4Tregs before the second treatment [0.75 (0-45.5) vs. 2.1 (0.1-90.8), P=0.0002]. Blood levels of PD-1Tregs and CTLA-4Tregs remained more or less decreased and increased during a 3-month therapy with nivolumab, respectively. Data of PD-1Tregs as well as CTLA-4Tregs was not significantly associated with frequencies of immune-related adverse events (P<0.05). In conclusion, we have demonstrated that circulating PD-1Tregs of melanoma patients in stage III rapidly and continuously decline after the initiation of adjuvant treatment with the PD-1 blocking antibody nivolumab. By contrast, this decline is paralleled with an increase of CTLA-4Tregs. The expression of PD-1 and CTLA-4 on Tregs might be a potential biomarker for the efficacy of immune checkpoint blockade in melanoma.