Cancer-germline antigen expression discriminates clinical outcome to CTLA-4 blockade Journal Article


Authors: Shukla, S. A.; Bachireddy, P.; Schilling, B.; Galonska, C.; Zhan, Q.; Bango, C.; Langer, R.; Lee, P. C.; Gusenleitner, D.; Keskin, D. B.; Babadi, M.; Mohammad, A.; Gnirke, A.; Clement, K.; Cartun, Z. J.; Van Allen, E. M.; Miao, D.; Huang, Y.; Snyder, A.; Merghoub, T.; Wolchok, J. D.; Garraway, L. A.; Meissner, A.; Weber, J. S.; Hacohen, N.; Neuberg, D.; Potts, P. R.; Murphy, G. F.; Lian, C. G.; Schadendorf, D.; Hodi, F. S.; Wu, C. J.
Article Title: Cancer-germline antigen expression discriminates clinical outcome to CTLA-4 blockade
Abstract: 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. 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. © 2018 Elsevier Inc.
Keywords: ipilimumab; melanoma; immunotherapy; ctla-4; autophagy; pd-1; mage-a; checkpoint blockade; cancer-germline antigen; immunogenomics
Journal Title: Cell
Volume: 173
Issue: 3
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2018-04-19
Start Page: 624
End Page: 633.e8
Language: English
DOI: 10.1016/j.cell.2018.03.026
PROVIDER: scopus
PUBMED: 29656892
DOI/URL:
Notes: Article -- Export Date: 1 May 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Jedd D Wolchok
    665 Wolchok
  2. Taha Merghoub
    206 Merghoub