| Literature DB >> 29656892 |
Sachet A Shukla1, Pavan Bachireddy2, Bastian Schilling3, Christina Galonska4, Qian Zhan5, Clyde Bango6, Rupert Langer7, Patrick C Lee6, Daniel Gusenleitner6, Derin B Keskin2, Mehrtash Babadi8, Arman Mohammad8, Andreas Gnirke8, Kendell Clement9, Zachary J Cartun6, Eliezer M Van Allen2, Diana Miao1, Ying Huang6, Alexandra Snyder10, Taha Merghoub10, Jedd D Wolchok10, Levi A Garraway2, Alexander Meissner11, Jeffrey S Weber12, Nir Hacohen8, Donna Neuberg13, Patrick R Potts14, George F Murphy5, Christine G Lian5, Dirk Schadendorf15, F Stephen Hodi16, Catherine J Wu17.
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.Entities:
Keywords: CTLA-4; MAGE-A; PD-1; autophagy; cancer-germline antigen; checkpoint blockade; immunogenomics; immunotherapy; ipilimumab; melanoma
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Year: 2018 PMID： 29656892 PMCID： PMC6044280 DOI： 10.1016/j.cell.2018.03.026
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582