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MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma

Rodig, Scott J., Gusenleitner, Daniel, Jackson, Donald G., Gjini, Evisa, Giobbie-Hurder, Anita, Jin, Chelsea, Chang, Han, Lovitch, Scott B., Horak, Christine, Weber, Jeffrey S., Weirather, Jason L., Wolchok, Jedd D., Postow, Michael A., Pavlick, Anna C., Chesney, Jason and Hodi, F. Stephen (2018) MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Science Translational Medicine, 10 (450). eaar3342. ISSN 1946-6234


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-γ (IFN-γ) and IFN-γ–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-γ–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.

Item Type: Article
Date Deposited: 04 Aug 2018 00:45
Last Modified: 04 Aug 2018 00:45


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