Tumor MHC expression guides first-line immunotherapy selection in melanoma

Elena Shklovskaya, Jenny H. Lee, Su Yin Lim, Ashleigh Stewart, Bernadette Pedersen, Peter Ferguson, Robyn P. M. Saw, John F. Thompson, Brindha Shivalingam, Matteo S. Carlino, Richard A. Scolyer, Alexander M. Menzies, Georgina V. Long, Richard F. Kefford, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma.

Original languageEnglish
Article number3374
Pages (from-to)1-13
Number of pages13
JournalCancers
Volume12
Issue number11
DOIs
Publication statusPublished - 14 Nov 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Anti-PD-1
  • Combination immunotherapy
  • Immune checkpoint blockade
  • Major histocompatibility (MHC) class I
  • Metastatic melanoma

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