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.
Author Info: (1) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (2) Division of Molecular Oncology & Immunology, The Netherl
Author Info: (1) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (2) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (3) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (4) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Department of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Oncode Institute, Utrecht, 3521 AL, The Netherlands. (5) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (6) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (7) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (8) University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095. (9) Department of Dermatology, University Hospital Duisburg-Essen, Essen D-45147, Germany. (10) Department of Dermatology, University Hospital Duisburg-Essen, Essen D-45147, Germany. Department of Dermatology, Venereology, and Allergology, University Hospital Wrzburg, Wrzburg 97080, Germany. (11) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Oncode Institute, Utrecht, 3521 AL, The Netherlands. (12) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (13) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. (14) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands; p.kvistborg@nki.nl.
