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CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity

Author

Listed:
  • Davide Bernareggi

    (University of California San Diego)

  • Qi Xie

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Westlake Institute for Advanced Study)

  • Briana C. Prager

    (University of California San Diego
    Cleveland Clinic Lerner College of Medicine at Cleveland Clinic & Case Western Reserve University)

  • Jiyoung Yun

    (University of California San Diego)

  • Luisjesus S. Cruz

    (University of California San Diego)

  • Timothy V. Pham

    (Center for Novel Therapeutics and Moores Cancer Center, UCSD)

  • William Kim

    (Center for Novel Therapeutics and Moores Cancer Center, UCSD
    University of California San Diego)

  • Xiqing Lee

    (Zhengzhou University People’s Hospital)

  • Michael Coffey

    (University of California San Diego)

  • Cristina Zalfa

    (The Scripps Research Institute)

  • Pardis Azmoon

    (University of California San Diego)

  • Huang Zhu

    (University of California San Diego)

  • Pablo Tamayo

    (Center for Novel Therapeutics and Moores Cancer Center, UCSD
    University of California San Diego)

  • Jeremy N. Rich

    (University of California San Diego)

  • Dan S. Kaufman

    (University of California San Diego)

Abstract

Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a “two cell type” whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.

Suggested Citation

  • Davide Bernareggi & Qi Xie & Briana C. Prager & Jiyoung Yun & Luisjesus S. Cruz & Timothy V. Pham & William Kim & Xiqing Lee & Michael Coffey & Cristina Zalfa & Pardis Azmoon & Huang Zhu & Pablo Tamay, 2022. "CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29469-0
    DOI: 10.1038/s41467-022-29469-0
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    References listed on IDEAS

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