Shukla et al. retrospectively analyzed RNA-seq data from melanoma biopsies and found that increased expression of a subcluster of MAGE-A cancer-germline genes predicted resistance to CTLA-4 (but not PD-1) blockade and correlated with lower OS and PFS. Further analysis suggested that MAGE-A was negatively associated with expression of LC3B and mutually exclusive with presence of HMGB1, indicating that MAGE-A suppressed autophagy and hence reduced T cell priming, contributing to clinical resistance to CTLA-4 blockade.

CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. (2) Department of Medical

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. (3) Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), 69121 Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Hospital Wurzburg, 97080 Wurzburg, Germany. (4) Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. (5) Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. (7) Department of Pathology, University of Bern, 3012 Bern, Switzerland. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. (11) Broad Institute, Cambridge, MA 02142, USA. (12) Broad Institute, Cambridge, MA 02142, USA. (13) Broad Institute, Cambridge, MA 02142, USA. (14) Broad Institute, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. (19) Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA. (20) Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA. (21) Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. (23) Broad Institute, Cambridge, MA 02142, USA; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. (24) New York University Langone Medical Center, New York, NY 10016, USA. (25) Broad Institute, Cambridge, MA 02142, USA. (26) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (27) Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. (28) Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (29) Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (30) Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), 69121 Heidelberg, Germany. (31) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. Electronic address: cwu@partners.org.

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