Danish Memon, Adam J Schoenfeld, Darwin Ye, George Fromm, Hira Rizvi, Xiang Zhang, Mohamed Reda Keddar, Divij Mathew, Kyung Jin Yoo, Jingya Qiu, Jayon Lihm, Jayalaksmi Miriyala, Jennifer L Sauter, Jia Luo, Andrew Chow, Umesh K Bhanot, Caroline McCarthy, Chad M 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 Beltrao, Taylor H Schreiber, Andy J Minn, Martin L Miller, Matthew D Hellmann
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...
February 12, 2024: Cancer Cell