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Acquired resistance to anti-PD1 therapy in patients with NSCLC reveals changes in T cell phenotypes and MET amplification


Hiltbrunner, Stefanie; Cords, Lena; Kasser, Sabrina; Freiberger, Sandra N; Kreutzer, Susanne; Toussaint, Nora C; Grob, Linda; Opitz, Isabelle; Messerli, Michael; Zoche, Martin; Soltermann, Alex; Rechsteiner, Markus; van den Broek, Maries; Bodenmiller, Bernd; Curioni-Fontecedro, Alessandra (2022). Acquired resistance to anti-PD1 therapy in patients with NSCLC reveals changes in T cell phenotypes and MET amplification. bioRxiv 487590v1, Cold Spring Harbor Laboratory.

Abstract

The treatment of non-small cell lung cancer (NSCLC) patients with immune checkpoint inhibitors has prolonged their survival dramatically. However, some patients develop resistance after initial response. Here, we used imaging mass cytometry and whole exome and RNA sequencing to analyze matching tumor samples from a cohort of NSCLC patients who initially responded to immune checkpoint inhibitor therapy and later developed acquired resistance. We detected two patterns of resistance: One group of patients had reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group showed high CD8+ T cell infiltration and high expression of PD-L1 and markedly elevated expression of other immune-inhibitory molecules. In two cases, we detected downregulation of type I and II IFN pathways after resistance developed, which could lead to an impaired anti-tumor immune response. This study adds to our knowledge of the mechanisms that cause resistance to immunotherapy in NSCLC patients.

Abstract

The treatment of non-small cell lung cancer (NSCLC) patients with immune checkpoint inhibitors has prolonged their survival dramatically. However, some patients develop resistance after initial response. Here, we used imaging mass cytometry and whole exome and RNA sequencing to analyze matching tumor samples from a cohort of NSCLC patients who initially responded to immune checkpoint inhibitor therapy and later developed acquired resistance. We detected two patterns of resistance: One group of patients had reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group showed high CD8+ T cell infiltration and high expression of PD-L1 and markedly elevated expression of other immune-inhibitory molecules. In two cases, we detected downregulation of type I and II IFN pathways after resistance developed, which could lead to an impaired anti-tumor immune response. This study adds to our knowledge of the mechanisms that cause resistance to immunotherapy in NSCLC patients.

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Item Type:Working Paper
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:10 April 2022
Deposited On:07 Jul 2022 13:05
Last Modified:22 Sep 2023 13:13
Series Name:bioRxiv
ISSN:2164-7844
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/2022.04.08.487590
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)