Synapse - Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer Journal Article

Authors:	Memon, D.; Schoenfeld, A. J.; Ye, D.; Fromm, G.; Rizvi, H.; Zhang, X.; Keddar, M. R.; Mathew, D.; Yoo, K. J.; Qiu, J.; Lihm, J.; Miriyala, J.; Sauter, J. L.; Luo, J.; Chow, A.; Bhanot, U. K.; McCarthy, C.; Vanderbilt, C. M.; Liu, C.; Abu-Akeel, M.; Plodkowski, A. J.; McGranahan, N.; Łuksza, M.; Greenbaum, B. D.; Merghoub, T.; Achour, I.; Barrett, J. C.; Stewart, R.; Beltrao, P.; Schreiber, T. H.; Minn, A. J.; Miller, M. L.; Hellmann, M. D.
Article Title:	Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer
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. © 2023 The Authors
Keywords:	signal transduction; genetics; mouse; animal; metabolism; animals; mice; carcinoma, non-small-cell lung; lung neoplasms; lung tumor; antigen presentation; immunotherapy; programmed death 1 ligand 1; non small cell lung cancer; tumor microenvironment; tumor heterogeneity; immune escape; clonal selection; humans; human; t cell exhaustion; neoantigens; anti-pd-1 therapy; immune-checkpoint blockade; b7-h1 antigen; genomics and transcriptomics; interferon alpha/gamma response; type i and type ii interferons
Journal Title:	Cancer Cell
Volume:	42
Issue:	2
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2024-02-12
Start Page:	209
End Page:	224.e9
Language:	English
DOI:	10.1016/j.ccell.2023.12.013
PUBMED:	38215748
PROVIDER:	scopus
PMCID:	PMC11249385
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85183996238&doi=10.1016%2fj.ccell.2023.12.013&partnerID=40&md5=7df3625d8a20e15cf16d39c415645dee
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Matthew Hellmann -- Source: Scopus