In biopsies of previously untreated melanoma, Rodig et al. found that loss of MHC-I expression on more than 50% of malignant cells was common, was associated with transcriptional repression of MHC-related genes, and predicted resistance to anti-CTLA-4 therapy, supporting a role for anti-CTLA-4 in CD8+ T cell priming. The expression of MHC class II on more than 1% of malignant cells or an IFNγ-related immune signature predicted superior response to anti-PD-1 therapy. Patients with the best overall responses to anti-PD-1 had higher baseline signatures for innate NK cells, γδ T cells, and IL-15.
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-gamma (IFN-gamma) and IFN-gamma-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-gamma-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.
Author Info: (1) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu. Department of Pathology, Brigham and Wome
Author Info: (1) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu. Department of Pathology, Brigham and Women's Hospital, Boston, MA 20115, USA. (2) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (3) Bristol-Myers Squibb, Princeton, NJ 08540, USA. (4) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Bristol-Myers Squibb, Princeton, NJ 08540, USA. (7) Bristol-Myers Squibb, Princeton, NJ 08540, USA. (8) Department of Pathology, Brigham and Women's Hospital, Boston, MA 20115, USA. (9) Bristol-Myers Squibb, Princeton, NJ 08540, USA. (10) Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. (11) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (13) Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. (14) Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. (15) James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. (16) Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA. srodig@bwh.harvard.edu stephen_hodi@dfci.harvard.edu.
