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Published OnlineFirst October 12, 2017; DOI: 10.1158/2159-8290.CD-17-0593 RESEARCH ARTICLE Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer Scott Gettinger 1 , 2 , Jungmin Choi 3 , Katherine Hastings 2 , Anna Truini 2 , Ila Datar 4 , Ryan Sowell 5 , Anna Wurtz2 , Weilai Dong 3 , Guoping Cai 4 , Mary Ann Melnick 2 , Victor Y. Du 5 , Joseph Schlessinger 2 , 6 , Sarah B. Goldberg1 , 2 , Anne Chiang 1 , 2 , Miguel F. Sanmamed 5 , Ignacio Melero 7 , 8 , Jackeline Agorreta 7 , 8 , Luis M. Montuenga7 , 8 , Richard Lifton 3 , Soldano Ferrone 9 , Paula Kavathas 2 , 5 , 10 , David L. Rimm 2 , 4 , Susan M. Kaech2 , 5 , Kurt Schalper 1 , 2 , 4 , Roy S. Herbst 1 , 2 , 6 , and Katerina Politi 1 , 2 , 4 ABSTRACT Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knock- out of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo , proving its role in resistance to ICIs.
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