Research ArticleCancer

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

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Science Translational Medicine  18 Jul 2018:
Vol. 10, Issue 450, eaar3342
DOI: 10.1126/scitranslmed.aar3342

MHC-ing immunotherapy response

Currently, there is no way to predict response to anti–CTLA-4 cancer immunotherapy. Using data from two published independent phase 2 clinical trials, Rodig et al. showed that MHC class I expression in advanced melanoma predicted resistance to anti–CTLA-4, but not anti-PD-1, treatment, which may need MHC class II to be effective. These results may explain why patients on combined therapy do better on average, with one drug overcoming the limitations of the other. The combination is also more toxic than single agents; knowing which drug to administer to which patients could make melanoma immunotherapy less taxing without sacrificing efficacy.


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.

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