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Cell. 2018 Apr 19;173(3):624-633.e8. doi: 10.1016/j.cell.2018.03.026. Epub 2018 Apr 12.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA.
3
Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), 69121 Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.
4
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
5
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
7
Department of Pathology, University of Bern, 3012 Bern, Switzerland.
8
Broad Institute, Cambridge, MA 02142, USA.
9
Broad Institute, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
10
Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA.
11
Broad Institute, Cambridge, MA 02142, USA; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
12
New York University Langone Medical Center, New York, NY 10016, USA.
13
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
14
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
15
Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
16
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA.
17
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02115, USA. Electronic address: cwu@partners.org.

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.

KEYWORDS:

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

PMID:
29656892
PMCID:
PMC6044280
[Available on 2019-04-19]
DOI:
10.1016/j.cell.2018.03.026

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