Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Stefanie Hiltbrunner, Lena Cords, Sabrina Kasser, Sandra N. Freiberger, Susanne Kreutzer, Nora C. Toussaint, Linda Grob, Isabelle Opitz, Michael Messerli, Martin Zoche, Alex Soltermann, Markus Rechsteiner, Maries Broek, Bernd Bodenmiller and Alessandra Curioni-Fontecedro ()
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Stefanie Hiltbrunner: University Hospital Zurich
Lena Cords: University of Zurich
Sabrina Kasser: University Hospital Zurich
Sandra N. Freiberger: University Hospital Zurich
Susanne Kreutzer: ETH and University of Zurich
Nora C. Toussaint: ETH Zurich
Linda Grob: ETH Zurich
Isabelle Opitz: University Hospital Zurich
Michael Messerli: University of Zurich
Martin Zoche: University Hospital Zurich
Alex Soltermann: University Hospital Zurich
Markus Rechsteiner: University Hospital Zurich
Maries Broek: University of Zurich
Bernd Bodenmiller: University of Zurich
Alessandra Curioni-Fontecedro: University Hospital Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC.

Date: 2023
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DOI: 10.1038/s41467-023-40745-5

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