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

• Published in: Oncoimmunology Vol. 11; no. 1; p. 2139074
• Main Authors: Ibáñez-Molero, Sofía, van Vliet, Alex, Pozniak, Joanna, Hummelink, Karlijn, Terry, Alexandra M., Monkhorst, Kim, Sanders, Joyce, Hofland, Ingrid, Landeloos, Ewout, Van Herck, Yannick, Bechter, Oliver, Kuilman, Thomas, Zhong, Weiwei, Marine, Jean-Christophe, Wessels, Lodewyk, Peeper, Daniel S.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2022; Taylor & Francis Group
• Subjects: Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Drug Resistance, Neoplasm - genetics; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; melanoma; Melanoma - drug therapy; Melanoma - genetics; Neoplasms - genetics; NSCLC; Original Research; Serine Proteinase Inhibitors - genetics; SERPINB9; Serpins - genetics; Skin Neoplasms; melanoma; SERPINB9; NSCLC; immunotherapy; Cancer
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2022.2139074

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.