Immune checkpoint inhibitors (ICIs) including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) antagonist antibodies for lung tumors mark a new era of cancer therapeutics harnessing a patient’s immune system to induce durable antitumor responses. Despite their impressive activity in some patients, challenges remain as most tumors exhibit primary or acquired resistance (AR) to ICIs, and the biologic mechanisms for resistance are poorly understood. Using a collection of 14 ICI-resistant lung cancer samples, we investigated whether alterations in genes encoding components of the HLA Class I antigen processing and presentation machinery or interferon signaling pathways play a role in AR to PD-1 or PD-L1 antagonistic antibodies. Although we did not detect any recurrent mutations or copy number changes in our AR cohort, we noted one case of an acquired homozygous loss of B2M that resulted in lack of HLA class I expression on the cell surface in both the patient’s tumor sample and the corresponding patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. To test if B2m expression confers sensitivity to ICIs in vivo, we used a CRISPR-mediated approach to knockout B2m in an ICI-sensitive, murine lung cancer cell line and transplanted the cells into syngeneic, immunocompetent mice. We found that the B2m knockout tumors were resistant to ICI therapy in contrast to the wild type tumors. Furthermore, RNA-seq analysis of a subset of the samples in the acquired resistance to ICI cohort revealed an inflammatory tumor microenvironment with significant upregulation of the inhibitory receptors LAG-3 and PD-1 in tumor-infiltrating T cells at ICI resistance. Overall, these findings provide a novel system for the evaluation and screening of candidate genes for their ability to mediate AR to ICIs in vivo. Moreover, they also provide evidence for the disruption of HLA Class I antigen processing and presentation as a mechanism for escape from ICIs in lung cancer and provide information on the immune microenvironment in ICI-resistant tumors.
Citation Format: Katherine Hastings, Scott Gettinger, Choi Jungmin, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Joseph Schlessinger, Sarah Goldberg, Anne Chiang, Ignacio Melero, Jackeline Agorreta, Luis Montuenga, Richard Lifton, Soldano Ferrone, Paula Kavathas, David Rimm, Susan Kaech, Kurt Schalper, Roy Herbst, Katerina Politi. Impaired HLA Class I antigen processing and presentation as a mechanism of acquired Rrsistance to immune checkpoint inhibitors in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A09.