Title |
Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade
|
---|---|
Published in |
Cell, April 2018
|
DOI | 10.1016/j.cell.2018.03.026 |
Pubmed ID | |
Authors |
Sachet A. Shukla, Pavan Bachireddy, Bastian Schilling, Christina Galonska, Qian Zhan, Clyde Bango, Rupert Langer, Patrick C. Lee, Daniel Gusenleitner, Derin B. Keskin, Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Zachary J. Cartun, Eliezer M. Van Allen, Diana Miao, Ying Huang, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Levi A. Garraway, Alexander Meissner, Jeffrey S. Weber, Nir Hacohen, Donna Neuberg, Patrick R. Potts, George F. Murphy, Christine G. Lian, Dirk Schadendorf, F. Stephen Hodi, Catherine J. Wu |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 42 | 27% |
United Kingdom | 7 | 4% |
Spain | 5 | 3% |
India | 5 | 3% |
Ireland | 3 | 2% |
Singapore | 3 | 2% |
Canada | 2 | 1% |
France | 2 | 1% |
Netherlands | 2 | 1% |
Other | 19 | 12% |
Unknown | 68 | 43% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 107 | 68% |
Scientists | 37 | 23% |
Practitioners (doctors, other healthcare professionals) | 10 | 6% |
Science communicators (journalists, bloggers, editors) | 4 | 3% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 277 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 76 | 27% |
Student > Ph. D. Student | 40 | 14% |
Other | 22 | 8% |
Student > Master | 16 | 6% |
Student > Bachelor | 16 | 6% |
Other | 40 | 14% |
Unknown | 67 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 57 | 21% |
Immunology and Microbiology | 49 | 18% |
Medicine and Dentistry | 42 | 15% |
Agricultural and Biological Sciences | 33 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 2% |
Other | 12 | 4% |
Unknown | 78 | 28% |