Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

By S. Gettinger, Jungmin Choi, K. Hastings, A. Truini, I. Datar, R. Sowell, A. Wurtz, W. Dong, G. Cai, Mary Ann Melnick and 16 more. Cancer Discovery, 2017

656 citations recorded by the source corpus.

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) 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. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/d27b1445acdcb1cb2d4bfe1a5f89fa7c1022eaee

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In Immunology

1. K. Rock
2. M. Hellmann
3. A. Schoenfeld

In Oncology

1. K. Rock
2. M. Hellmann
3. A. Schoenfeld

Citations in the corpus

• Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation (2021, background): “low, loss of MHC I antigen presentation results in resistance to checkpoint blockade (141).”
• Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “While some reports require initial partial or complete response to ICI, others include cases of initial stable disease or “mixed responses” (Gettinger et al., 2017; Iams et al., 2019; Kakavand et al., 2017).”