CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity

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 Tamayo, Jeremy N. Rich and Dan S. Kaufman ()
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Davide Bernareggi: University of California San Diego
Qi Xie: Westlake University
Briana C. Prager: University of California San Diego
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
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
Jeremy N. Rich: University of California San Diego
Dan S. Kaufman: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29469-0

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