Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Moshe Sade-Feldman, Yunxin J. Jiao, Jonathan H. Chen, Michael S. Rooney, Michal Barzily-Rokni, Jean-Pierre Eliane, Stacey L. Bjorgaard, Marc R. Hammond, Hans Vitzthum, Shauna M. Blackmon, Dennie T. Frederick, Mehlika Hazar-Rethinam, Brandon A. Nadres, Emily E. Seventer, Sachet A. Shukla, Keren Yizhak, John P. Ray, Daniel Rosebrock, Dimitri Livitz, Viktor Adalsteinsson, Gad Getz, Lyn M. Duncan, Bo Li, Ryan B. Corcoran, Donald P. Lawrence, Anat Stemmer-Rachamimov, Genevieve M. Boland, Dan A. Landau, Keith T. Flaherty, Ryan J. Sullivan () and Nir Hacohen ()
Additional contact information
Moshe Sade-Feldman: Massachusetts General Hospital Cancer Center
Yunxin J. Jiao: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Jonathan H. Chen: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Michael S. Rooney: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Michal Barzily-Rokni: Massachusetts General Hospital Cancer Center
Jean-Pierre Eliane: Massachusetts General Hospital
Stacey L. Bjorgaard: Massachusetts General Hospital Cancer Center
Marc R. Hammond: Massachusetts General Hospital Cancer Center
Hans Vitzthum: Massachusetts General Hospital Cancer Center
Shauna M. Blackmon: Massachusetts General Hospital Cancer Center
Dennie T. Frederick: Massachusetts General Hospital Cancer Center
Mehlika Hazar-Rethinam: Massachusetts General Hospital Cancer Center
Brandon A. Nadres: Massachusetts General Hospital Cancer Center
Emily E. Seventer: Massachusetts General Hospital Cancer Center
Sachet A. Shukla: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Keren Yizhak: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
John P. Ray: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Daniel Rosebrock: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Dimitri Livitz: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Viktor Adalsteinsson: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Gad Getz: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Lyn M. Duncan: Massachusetts General Hospital
Bo Li: Dana-Farber Cancer Institute
Ryan B. Corcoran: Massachusetts General Hospital Cancer Center
Donald P. Lawrence: Massachusetts General Hospital Cancer Center
Anat Stemmer-Rachamimov: Massachusetts General Hospital
Genevieve M. Boland: Massachusetts General Hospital
Dan A. Landau: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard
Keith T. Flaherty: Massachusetts General Hospital Cancer Center
Ryan J. Sullivan: Massachusetts General Hospital Cancer Center
Nir Hacohen: Massachusetts General Hospital Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

Date: 2017
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DOI: 10.1038/s41467-017-01062-w

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