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Gangaev A, Rozeman EA, Rohaan MW, et al. Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response. Proc Natl Acad Sci U S A. 2021;118(43)doi: 10.1073/pnas.2102849118.
Gangaev, A., Rozeman, E. A., Rohaan, M. W., Isaeva, O. I., Philips, D., Patiwael, S., van den Berg, J. H., Ribas, A., Schadendorf, D., Schilling, B., Schumacher, T. N., Blank, C. U., Haanen, J. B. A. G., & Kvistborg, P. (2021). Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response. Proceedings of the National Academy of Sciences of the United States of America, 118(43), . https://doi.org/10.1073/pnas.2102849118
Gangaev, Anastasia, et al. "Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response." Proceedings of the National Academy of Sciences of the United States of America vol. 118,43 (2021). doi: https://doi.org/10.1073/pnas.2102849118
Gangaev A, Rozeman EA, Rohaan MW, Isaeva OI, Philips D, Patiwael S, van den Berg JH, Ribas A, Schadendorf D, Schilling B, Schumacher TN, Blank CU, Haanen JBAG, Kvistborg P. Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response. Proc Natl Acad Sci U S A. 2021 Oct 26;118(43). doi: 10.1073/pnas.2102849118. PMID: 34670835.
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Proc Natl Acad Sci U S A. 2021 Oct 26;118(43). doi: 10.1073/pnas.2102849118.

Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response.

Proceedings of the National Academy of Sciences of the United States of America

Anastasia Gangaev, Elisa A Rozeman, Maartje W Rohaan, Olga I Isaeva, Daisy Philips, Sanne Patiwael, Joost H van den Berg, Antoni Ribas, Dirk Schadendorf, Bastian Schilling, Ton N Schumacher, Christian U Blank, John B A G Haanen, Pia Kvistborg

Affiliations

  1. Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
  2. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
  3. Department of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
  4. Oncode Institute, Utrecht, 3521 AL, The Netherlands.
  5. University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
  6. Department of Dermatology, University Hospital Duisburg-Essen, Essen D-45147, Germany.
  7. Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg 97080, Germany.
  8. Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands; [email protected].

PMID: 34670835 DOI: 10.1073/pnas.2102849118

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.

Keywords: CTLA-4; PD-1; melanoma-reactive CD8 T cells

Conflict of interest statement

The authors declare no competing interest.

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