Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Oct 27

PMID 29070816

Citations 496

Authors

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 Van 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

Nir Hacohen

Affiliations

Soon will be listed here.

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.

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