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

David H. Peng, B. Leticia Rodriguez, Lixia Diao, Pierre-Olivier Gaudreau, Aparna Padhye, Jessica M. Konen, Joshua K. Ochieng, Caleb A. Class, Jared J. Fradette, Laura Gibson, Limo Chen, Jing Wang, Lauren A. Byers and Don. L. Gibbons ()
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David H. Peng: The University of Texas MD Anderson Cancer Center
B. Leticia Rodriguez: The University of Texas MD Anderson Cancer Center
Lixia Diao: The University of Texas MD Anderson Cancer Center
Pierre-Olivier Gaudreau: The University of Texas MD Anderson Cancer Center
Aparna Padhye: The University of Texas MD Anderson Cancer Center
Jessica M. Konen: The University of Texas MD Anderson Cancer Center
Joshua K. Ochieng: The University of Texas MD Anderson Cancer Center
Caleb A. Class: The University of Texas MD Anderson Cancer Center
Jared J. Fradette: The University of Texas MD Anderson Cancer Center
Laura Gibson: The University of Texas MD Anderson Cancer Center
Limo Chen: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Lauren A. Byers: The University of Texas MD Anderson Cancer Center
Don. L. Gibbons: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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 patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.

Date: 2021
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DOI: 10.1038/s41467-021-22875-w

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