Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer
Danish Memon, Adam J. Schoenfeld, Darwin Ye, George Fromm, Hira Rizvi, Xiang H.-F. Zhang, Mohamed Reda Keddar, Divij Mathew, Kyung Jin Yoo, Jingya Qiu, Jayon Lihm, Jayalaksmi Miriyala, Jennifer L. Sauter, Jia Luo, Andrew Chow, Umesh Bhanot, Caroline G. McCarthy, Chad Vanderbilt, Cailian Liu, Mohsen Abu-Akeel, Andrew J. Plodkowski, Nicholas McGranahan, Marta Łuksza, Benjamin D. Greenbaum, Taha Merghoub, Ikbel Achour, J. Carl Barrett, Ross Stewart, Pedro Beltrão, Taylor H. Schreiber, Andy J. Minn, Martin L. Miller, Matthew D. Hellmann
Abstract
Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.