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

Author

Listed:
  • David H. Peng

    (The University of Texas MD Anderson Cancer Center
    Perlmutter Cancer Center, NYU Langone Health, 550 First Avenue, Smilow Building 10th Floor, Suite 1010)

  • 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
    Research Institute of the McGill University Health Centre)

  • Aparna Padhye

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences)

  • 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
    The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • 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 & Jin, 2021. "Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22875-w
    DOI: 10.1038/s41467-021-22875-w
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    Cited by:

    1. Jae Eun Choi & Yuanyuan Qiao & Ilona Kryczek & Jiali Yu & Jonathan Gurkan & Yi Bao & Mahnoor Gondal & Jean Ching-Yi Tien & Tomasz Maj & Sahr Yazdani & Abhijit Parolia & Houjun Xia & JiaJia Zhou & Shua, 2024. "PIKfyve, expressed by CD11c-positive cells, controls tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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