Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade

• Published in: Cell Vol. 173; no. 3; pp. 624 - 633.e8
• Main Authors: Shukla, Sachet A., Bachireddy, Pavan, Schilling, Bastian, Galonska, Christina, Zhan, Qian, Bango, Clyde, Langer, Rupert, Lee, Patrick C., Gusenleitner, Daniel, Keskin, Derin B., Babadi, Mehrtash, Mohammad, Arman, Gnirke, Andreas, Clement, Kendell, Cartun, Zachary J., Van Allen, Eliezer M., Miao, Diana, Huang, Ying, Snyder, Alexandra, Merghoub, Taha, Wolchok, Jedd D., Garraway, Levi A., Meissner, Alexander, Weber, Jeffrey S., Hacohen, Nir, Neuberg, Donna, Potts, Patrick R., Murphy, George F., Lian, Christine G., Schadendorf, Dirk, Hodi, F. Stephen, Wu, Catherine J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.04.2018
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Autophagy; cancer-germline antigen; Cell Line, Tumor; checkpoint blockade; CTLA-4; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Profiling; Germ-Line Mutation; Humans; immunogenomics; Immunotherapy; ipilimumab; Ipilimumab - pharmacology; MAGE-A; Male; melanoma; Melanoma - genetics; Melanoma - immunology; Melanoma-Specific Antigens - genetics; Melanoma-Specific Antigens - immunology; Mice; Mice, Transgenic; Neoplasms - genetics; Neoplasms - immunology; PD-1; Skin Neoplasms - genetics; Skin Neoplasms - immunology; immunogenomics; checkpoint blockade; cancer-germline antigen; autophagy; ipilimumab; immunotherapy; melanoma; CTLA-4; MAGE-A; PD-1
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.03.026

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. [Display omitted] •Increased expression of a MAGE-A subcluster predicts resistance to CTLA-4 blockade•This MAGE-A subcluster marks a distinct, epigenetically defined subset of melanomas•This gene signature is specific to resistance to CTLA-4, but not PD-1, blockade•Autophagy is implicated in clinical resistance to CTLA-4 blockade Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.