Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer

Scott Gettinger, Jungmin Choi, Katherine Hastings, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Victor Y. Du, Joseph Schlessinger, Sarah B. Goldberg, Anne Chiang, Miguel F. Sanmamed, Ignacio Melero, Jackeline Agorreta, Luis M. Montuenga, Richard Lifton, Soldano FerronePaula Kavathas, David L. Rimm, Susan M. Kaech, Kurt Schalper, Roy S. Herbst, Katerina Politi

Research output: Contribution to journalArticlepeer-review

231 Citations (Scopus)

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 knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer. SIGNIFICANCE: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer.

Original languageEnglish
Pages (from-to)1420-1435
Number of pages16
JournalCancer Discovery
Volume7
Issue number12
DOIs
Publication statusPublished - 2017 Dec
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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