Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment

Falcomata, Chiara; Baerthel, Stefanie; Widholz, Sebastian A.; Schneeweis, Christian; Montero, Juan Jose; Toska, Albulena; Mir, Jonas; Kaltenbacher, Thorsten; Heetmeyer, Jeannine; Swietlik, Jonathan J.; Cheng, Jing-Yuan; Teodorescu, Bianca; Reichert, Oliver; Schmitt, Constantin; Grabichler, Kathrin; Coluccio, Andrea; Boniolo, Fabio; Veltkamp, Christian; Zukowska, Magdalena; Vargas, Angelica Arenas; Paik, Woo Hyun; Jesinghaus, Moritz; Steiger, Katja; Maresch, Roman; Oellinger, Rupert; Ammon, Tim; Baranov, Olga; Robles, Maria S.; Rechenberger, Julia; Kuster, Bernhard; Meissner, Felix; Reichert, Maximilian; Flossdorf, Michael; Rad, Roland; Schmidt-Supprian, Marc; Schneider, Guenter und Saur, Dieter (2022): Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. In: Nature Cancer, Bd. 3, Nr. 3: S. 318-336

Abstract

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype. Saur and colleagues perform a high-throughput combinatorial drug screen and identify a synergistic combination between nintedanib and trametinib that sensitizes mesenchymal PDAC to immune checkpoint blockade.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 329628492
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 395357507