SERPINB9 is commonly amplified and high expression in cancer cells correlates with poor immune checkpoint blockade response

Autor: Sofía Ibáñez-Molero, Alex van Vliet, Joanna Pozniak, Karlijn Hummelink, Alexandra M. Terry, Kim Monkhorst, Joyce Sanders, Ingrid Hofland, Ewout Landeloos, Yannick Van Herck, Oliver Bechter, Thomas Kuilman, Weiwei Zhong, Jean-Christophe Marine, Lodewyk Wessels, Daniel S. Peeper
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: OncoImmunology, Vol 11, Iss 1 (2022)
Druh dokumentu: article
ISSN: 2162402X
2162-402X
DOI: 10.1080/2162402X.2022.2139074
Popis: Immunotherapies, in particular immune checkpoint blockade (ICB), have improved the clinical outcome of cancer patients, although many fail to mount a durable response. Several resistance mechanisms have been identified, but our understanding of the requirements for a robust ICB response is incomplete. We have engineered an MHC I/antigen: TCR-matched panel of human NSCLC cancer and T cells to identify tumor cell-intrinsic T cell resistance mechanisms. The top differentially expressed gene in resistant tumor cells was SERPINB9. This serine protease inhibitor of the effector T cell-derived molecule granzyme B prevents caspase-mediated tumor apoptosis. Concordantly, we show that genetic ablation of SERPINB9 reverts T cell resistance of NSCLC cell lines, whereas its overexpression reduces T cell sensitivity. SERPINB9 expression in NSCLC strongly correlates with a mesenchymal phenotype. We also find that SERPINB9 is commonly amplified in cancer, particularly melanoma in which it is indicative of poor prognosis. Single-cell RNA sequencing of ICB-treated melanomas revealed that SERPINB9 expression is elevated not only in cells from post- versus pre-treatment cancers, but also in ICB-refractory cancers. In NSCLC we commonly observed rare SERPINB9-positive cancer cells, possibly accounting for reservoirs of ICB-resistant cells. While underscoring SERPINB9 as a potential target to combat immunotherapy resistance, these results suggest its potential to serve as a prognostic and predictive biomarker.
Databáze: Directory of Open Access Journals
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