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

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Impaired HLA Class I Antigen Processing and Presentation As a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer 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 Gettinger1,2, Jungmin Choi3, Katherine Hastings2, Anna Truini2, Ila Datar4, Ryan Sowell5, Anna Wurtz2, Weilai Dong3, Guoping Cai4, Mary Ann Melnick2, Victor Y. Du5, Joseph Schlessinger2,6, Sarah B. Goldberg1,2, Anne Chiang1,2, Miguel F. Sanmamed5, Ignacio Melero7,8, Jackeline Agorreta7,8, Luis M. Montuenga7,8, Richard Lifton3, Soldano Ferrone9, Paula Kavathas2,5,10, David L. Rimm2,4, Susan M. Kaech2,5, Kurt Schalper1,2,4, Roy S. Herbst1,2,6, and Katerina Politi1,2,4 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. 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. Cancer Discov; 7(12); 1–16. ©2017 AACR. 1Department of Medicine (Section of Medical Oncology), Yale University S. Gettinger, J. Choi, K. Hastings, A. Truini, and I. Datar contributed equally School of Medicine, New Haven, Connecticut. 2Yale Cancer Center, Yale to this article. 3 University School of Medicine, New Haven, Connecticut. Department of Current address for R. Lifton: The Rockefeller University, New York, Genetics, Yale University School of Medicine, New Haven, Connecticut. New York. 4Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. 5Department of Immunobiology, Yale University School of Corresponding Authors: Katerina Politi, Yale University School of Med- Medicine, New Haven, Connecticut. 6Department of Pharmacology, Yale icine, 333 Cedar Street, SHM-I 234D, New Haven, CT 06510. Phone: University School of Medicine, New Haven, Connecticut. 7CIMA and Clinica 203-737-5921, Fax: 203-785-7531; E-mail: [email protected]; and Universidad de Navarra, Pamplona, Spain. 8Centro de Investigación Scott Gettinger, Department of Internal Medicine (Section of Medical Biomédica en red de Oncología CIBERONC, Madrid, Spain. 9Department Oncology), Yale Cancer Center, Yale University School of Medicine, New of Surgery, Massachusetts General Hospital, Harvard Medical School, Haven, CT 06520. Phone: 203-737-6980; Fax: 203-785-3788; E-mail: Boston, Massachusetts. 10Department of Laboratory Medicine, Yale [email protected] University School of Medicine, New Haven, Connecticut. doi: 10.1158/2159-8290.CD-17-0593 Note: Supplementary data for this article are available at Cancer Discovery ©2017 American Association for Cancer Research. Online (http://cancerdiscovery.aacrjournals.org/). OF1 | CANCER DISCOVERY DECEMBER 2017 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 12, 2017; DOI: 10.1158/2159-8290.CD-17-0593 INTRODUCTION with such therapy to date showed an unprecedented 16 percent 5-year survival rate among patients with pretreated Recent regulatory agency approvals of immune check- advanced NSCLC (13). Currently, the anti–PD-1 agent pem- point inhibitors (ICI), including programmed death 1 (PD-1), brolizumab is approved for use as first- and second-line programmed death ligand 1 (PD-L1), and cytotoxic T-lym- therapy in patients with advanced NSCLCs whose tumors phocyte associated protein 4 (CTLA4) antagonist antibod- express PD-L1 using IHC (10, 11). The PD-1 axis block- ies for multiple advanced solid tumors, have marked a new ers nivolumab (anti–PD-1) and atezolizumab (anti–PD-L1) era of cancer therapeutics that will increasingly harness a are additionally indicated for use as second-line therapy in patient’s immune system to kill and control malignancy patients with NSCLC regardless of tumor PD-L1 expression (1). The PD-1 receptor on cytotoxic T cells suppresses (6, 8). Anti-CTLA4–directed therapies, like ipilimumab and their activity when bound by its ligands PD-L1 or PD-L2 tremelimumab, have shown limited activity as single agents (2, 3). Disruption of this negative signal using anti–PD-1 in lung cancer (14, 15). However, early-phase studies using the or anti–PD-L1 antibodies unleashes T-cell effector proper- combination of CTLA4 and PD-1 axis inhibitors in patients ties that lead to tumor cell killing. Similarly, blockade of with advanced NSCLC have shown encouraging results (16, the T cell–inhibitory molecule CTLA4 stimulates tumor 17). Despite the impressive activity of PD-1 axis inhibitors in antigen-specific immune responses by suppressing inhibi- some patients with advanced NSCLC, most patients will not tory signals on naïve T cells and through elimination of benefit from therapy, and the majority of those who respond regulatory T cells (4). will ultimately develop drug-resistant tumors. PD-1 axis antagonist antibodies in non–small cell lung Little is known about mechanisms mediating primary cancer (NSCLC) can induce durable antitumor responses and acquired resistance to ICIs in lung cancer. Low nonsyn- (median duration of response, 12–25 months; refs. 5–12), onymous mutation burden has been associated with primary with some responses lasting well beyond 5 years (13). The resistance to these therapies in melanoma and lung can- longest follow-up study of patients with NSCLC treated cer (18–20). In NSCLC, tumors with nondetectable PD-L1 December 2017 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 12, 2017; DOI: 10.1158/2159-8290.CD-17-0593 RESEARCH ARTICLE Gettinger et al. ABAnti–PD-L1/ EGFR TKI/anti–PD-1 anti-CTLA4 (after progression on n = 1 EGFR TKI) n = 1 ICI treatment ICI treatment Anti–PD-L1 Anti–PD-1 n = 4 n = 6 Pretreatment Response Resistance (+/− Intervening therapy) Tumor tissue Tumor tissue Germline DNA PDX Anti–PD-1/ anti-CTLA4 n = 2 C Analysis 14 16 Exome sequencing 11 RNA sequencing Quantitative immunofluorescence 18 24 17 10 1 On immunotherapy Patient 22 Off immunotherapy without Identification of other systemic therapy 19 Partial response resistance-specific 8 alterations Mixed response 13 Acquired resistance 23 Biopsy 26 020406080 100 120 140 160 180 200 Time (weeks) Figure 1. Analytic process and characteristics of the cohort of cases of acquired resistance to ICIs. A, Schematic representation of the repeat biopsy program and sample analysis. Tumor specimens (and corresponding PDXs when available) collected at the time of resistance to ICIs and before treatment with ICIs along with germline DNA were analyzed using whole-exome sequencing. For select samples with sufficient material, RNA sequencing and quan- titative immunofluorescence were also performed. B, Pie chart illustrating the types of therapies received by patients in this study. C, Swimmer’s plot indicating time of response, resistance to ICIs, and length of time on therapy for individual patients. expression are also less responsive to these agents, although RESULTS there is variability depending on the biomarker used (6, 8, 10). Whether these factors are also involved in acquired The Genomic Landscape of ICI-Resistant Tumors resistance to ICIs has not been established. In lung cancer, To identify cellular and molecular mechanisms associated to date, neoantigen loss has been associated with acquired with acquired ICI resistance, we analyzed ICI-resistant NSCLCs resistance to immune checkpoint blockade (21). In mela- collected systematically at our institution between 2011 and noma, acquired resistance to PD-1 inhibitors can be medi- 2016 as part of a repeat biopsy program focused on thoracic ated by tumor cell–autonomous defects in interferon (IFN) malignancies. We performed whole-exome DNA sequencing signaling through JAK1/2-inactivating mutations or defec- on available tumor samples collected from 14 patients at the tive HLA Class I antigen processing through deleterious time of resistance to PD-1 axis inhibitors, given either alone mutations in Beta-2 microglobulin (B2M; ref. 22). Further (n = 10), in combination with a CTLA4 inhibitor (n = 3), or underscoring the importance of these pathways for resist- with the tyrosine kinase inhibitor erlotinib after progres- ance to ICIs, defects in the IFN signaling pathway have sion on erlotinib alone (n = 1; Fig. 1A and B). For three of also been found in melanomas with primary resistance
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