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

Shukla, S. A., Bachireddy, P., Schilling, B., Galonska, C., Zhan, Q., Bango, C., et al. (2018). Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. Cell, 173(3): e8, pp. 624-633. doi:10.1016/j.cell.2018.03.026.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-4B90-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-4B94-2
Genre: Journal Article

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 Creators:
Shukla, Sachet A. , Author
Bachireddy, Pavan , Author
Schilling, Bastian , Author
Galonska, Christina1, Author              
Zhan, Qian , Author
Bango, Clyde , Author
Langer, Rupert , Author
Lee, Patrick C., Author
Gusenleitner, Daniel , Author
Keskin, Derin B. , Author
Babadi, Mehrtash , Author
Mohammad, Arman , Author
Gnirke, Andreas , Author
Clement, Kendell , Author
Cartun, Zachary J. , Author
Van Allen, Eliezer M. , Author
Miao, Diana , Author
Huang, Ying , Author
Snyder, Alexandra , Author
Merghoub, Taha , Author
Wolchok, Jedd D. , AuthorGarraway, Levi A. , AuthorMeissner, Alexander1, 2, 3, Author              Weber, Jeffrey S. , AuthorHacohen, Nir , AuthorNeuberg, Donna , AuthorPotts, Patrick R. , AuthorMurphy, George F. , AuthorLian, Christine G. , AuthorSchadendorf, Dirk , AuthorHodi, F. Stephen , AuthorWu, Catherine J. , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Broad Institute, Cambridge, MA 02142, USA, ou_persistent22              
3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA, ou_persistent22              

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Free keywords: CTLA-4; MAGE-A; PD-1; autophagy; cancer-germline antigen; checkpoint blockade; immunogenomics; immunotherapy; ipilimumab; melanoma
 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.

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Language(s): eng - English
 Dates: 2018-03-132018-04-12
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.cell.2018.03.026
 Degree: -

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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: 10 Volume / Issue: 173 (3) Sequence Number: e8 Start / End Page: 624 - 633 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183