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.
Bibliographical noteFunding Information:
This work was supported by the following NIH/NCI grants: the Yale SPORE in Lung Cancer (P50CA196530) to R.S. Herbst, R01CA195720 to K. Politi and S.M. Kaech, and F32CA210516 to K. Hastings. Additional support came from a Stand Up To Cancer Lung Dream grant, Department of Defense Lung Cancer Research Program Career Development Award #LC150383 to K. Schalper, a Lung Cancer Research Foundation grant to K. Schalper, a fellowship from the Italian Association for Cancer Research (AIRC) to A. Truini, the Leslie H. Warner Fellowship to K. Hastings, The Diane and David Heller Foundation, The Beatrice Klienberg Neuwirth Research Program, and the Melissa Marottoli Hogan Foundation. Yale Cancer Center Shared Resources used in this article were in part supported by NIH/NCI Cancer Center Support Grant P30 CA016359.
S. Gettinger is a consultant/advisory board member for BMS, ARIAD, and Pfizer. S.B. Goldberg is a consultant/advisory board member for AstraZeneca. I. Melero reports receiving commercial research grants from Alligator, BMS, and Roche and is a consultant/advisory board member for BMS, Roche, Alligator, Bayer, Lilly, Novartis, and AstraZeneca. D.L. Rimm is a consultant/advisory board member for Perkin Elmer, BMS, AstraZeneca, Cell Signaling Technology, and Merck. K.A. Schalper reports receiving commercial research grants from Tesaro Inc., Onkaido Therapeutics, Takeda, and Surface Oncology, has received honoraria from the speakers bureaus of Takeda and Merck, and is a consultant/advisory board member for Celgene. K. Politi reports receiving commercial research grants from AstraZeneca and Roche and is a consultant/advisory board member for AstraZeneca, Novartis, and Merck. No potential conflicts of interest were disclosed by the other authors.
© 2017 American Association for Cancer Research.
ASJC Scopus subject areas