To investigate the mechanisms of ICB on tumor-reactive CD8+ T cells, Gangaev et al. quantitated the frequency and breadth of CD8+ T cell responses to 71 melanoma epitopes in peripheral blood from 24 melanoma patients, pre- and on-therapy with anti-PD-1. PD-1 blockade did not alter the frequency or the TCR repertoire of circulating melanoma reactive CD8+ T cells. In 9 patients treated with anti-CTLA-4, while anti-CTLA-4 had no effect on the frequency of circulating CD8+ T cells, it significantly increased the melanoma T cell repertoire, suggesting that PD-1 and CTLA-4 blockade have distinct mechanisms, with anti-PD-1 likely working primarily at the tumor site.
Contributed by Katherine Turner
ABSTRACT: Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.