MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma Journal Article
| Authors: | Rodig, S. J.; Gusenleitner, D.; Jackson, D. G.; Gjini, E.; Giobbie-Hurder, A.; Jin, C.; Chang, H.; Lovitch, S. B.; Horak, C.; Weber, J. S.; Weirather, J. L.; Wolchok, J. D.; Postow, M. A.; Pavlick, A. C.; Chesney, J.; Hodi, F. S. |
| Article Title: | MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma |
| Abstract: | Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti-CTLA-4, anti-PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti-CTLA-4, but not anti-PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon- (IFN-) and IFN-mediated gene signatures, and predicted response to anti-PD-1, but not anti-CTLA-4, therapy. We conclude that primary response to anti-CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti-PD-1 is associated with preexisting IFN-mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity. Copyright © 2018 The Authors, some rights reserved. |
| Journal Title: | Science Translational Medicine |
| Volume: | 10 |
| Issue: | 450 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2018-07-18 |
| Start Page: | eaar3342 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.aar3342 |
| PROVIDER: | scopus |
| PUBMED: | 30021886 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 September 2018 -- Source: Scopus |
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