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

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

doi:10.1016/j.cell.2018.03.026

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

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

Authors

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

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antibodies, Monoclonal / therapeutic use
Antigens, Neoplasm / genetics
Antigens, Neoplasm / immunology
Autophagy
CTLA-4 Antigen / genetics*
CTLA-4 Antigen / immunology*
Cell Line, Tumor
DNA Methylation
Epigenesis, Genetic*
Female
Gene Expression Profiling
Germ-Line Mutation*
Humans
Immunotherapy
Ipilimumab / pharmacology
Male
Melanoma / genetics
Melanoma / immunology
Melanoma-Specific Antigens / genetics
Melanoma-Specific Antigens / immunology
Mice
Mice, Transgenic
Neoplasms / genetics*
Neoplasms / immunology*
Skin Neoplasms / genetics
Skin Neoplasms / immunology

Substances

Antibodies, Monoclonal
Antigens, Neoplasm
CTLA-4 Antigen
CTLA4 protein, human
Ipilimumab
MAGEA1 protein, human
Melanoma-Specific Antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding