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Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers

By David H. Peng, B. Leticia Rodriguez, Lixia Diao, Pierre-Olivier Gaudreau, Aparna Padhye, Joshua Ochieng Kapere, Caleb A. Class, Jared J. Fradette, Laura Gibson, Limo Chen, Jing Wang, Lauren A. Byers, Don. L Gibbons

Posted 07 Jun 2020
bioRxiv DOI: 10.1101/2020.06.07.136366

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in melanoma patients treated with PD-1 blockade predicted poorer overall survival and response. Our study validates a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade ### Competing Interest Statement D.L.G. declares advisory board work for Janssen, AstraZeneca, GlaxoSmithKline and Sanofi. D.L.G. receives research grant funding from AstraZeneca, Janssen, Astellas, Ribon Therapeutics and Takeda. L.A.B. declares consulting work for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar, SA. L.A.B. receives research grant funding from AbbVie, AstraZeneca, GenMab, Tolero Pharmaceuticals. All other authors declare that they have no conflict of interests.

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