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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 language | English |
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Article number | 3374 |
Pages (from-to) | 1-13 |
Number of pages | 13 |
Journal | Cancers |
Volume | 12 |
Issue number | 11 |
DOIs | |
Publication status | Published - 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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Molecular determinants of risk, progression and treatment response in melanoma
Kefford, R., Thompson, J., Hersey, P., Mann, G., Scolyer, R., Hayward, N. & Long, G.
1/01/16 → …
Project: Research