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Sci Transl Med. 2018 Jul 18;10(450). pii: eaar3342. doi: 10.1126/scitranslmed.aar3342.

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

Author information

1
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu.
2
Department of Pathology, Brigham and Women's Hospital, Boston, MA 20115, USA.
3
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Bristol-Myers Squibb, Princeton, NJ 08540, USA.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
7
Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
9
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
10
Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu.

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-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.

Comment in

PMID:
30021886
DOI:
10.1126/scitranslmed.aar3342
[Indexed for MEDLINE]

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