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Cell DOI:10.1016/j.cell.2018.03.026

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

Publication TypeJournal Article
Year of Publication2018
AuthorsShukla, SA, Bachireddy, P, Schilling, B, Galonska, C, Zhan, Q, Bango, C, Langer, R, Lee, PC, Gusenleitner, D, Keskin, DB, Babadi, M, Mohammad, A, Gnirke, A, Clement, K, Cartun, ZJ, Van Allen, EM, Miao, D, Huang, Y, Snyder, A, Merghoub, T, Wolchok, JD, Garraway, LA, Meissner, A, Weber, JS, Hacohen, N, Neuberg, D, Potts, PR, Murphy, GF, Lian, CG, Schadendorf, D, F Hodi, S, Wu, CJ
Date Published2018 04 19
KeywordsAnimals, Antibodies, Monoclonal, Antigens, Neoplasm, Autophagy, Cell Line, Tumor, CTLA-4 Antigen, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Germ-Line Mutation, Humans, Immunotherapy, Ipilimumab, Male, Melanoma, Melanoma-Specific Antigens, Mice, Mice, Transgenic, Neoplasms, Skin Neoplasms

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.


Alternate JournalCell
PubMed ID29656892
PubMed Central IDPMC6044280
Grant List / HHMI / Howard Hughes Medical Institute / United States
R01 HL103532 / HL / NHLBI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R50 CA211482 / CA / NCI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
R01 DA036898 / DA / NIDA NIH HHS / United States