In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

Dzana Dervovic, Ahmad A. Malik, Edward L. Y. Chen, Masahiro Narimatsu, Nina Adler, Somaieh Afiuni-Zadeh, Dagmar Krenbek, Sebastien Martinez, Ricky Tsai, Jonathan Boucher, Jacob M. Berman, Katie Teng, Arshad Ayyaz, YiQing Lü, Geraldine Mbamalu, Sampath K. Loganathan, Jongbok Lee, Li Zhang, Cynthia Guidos, Jeffrey Wrana, Arschang Valipour, Philippe P. Roux, Jüri Reimand, Hartland W. Jackson and Daniel Schramek ()
Additional contact information
Dzana Dervovic: Mount Sinai Hospital
Ahmad A. Malik: Mount Sinai Hospital
Edward L. Y. Chen: Mount Sinai Hospital
Masahiro Narimatsu: Mount Sinai Hospital
Nina Adler: Computational Biology Program, Ontario Institute for Cancer Research
Somaieh Afiuni-Zadeh: Mount Sinai Hospital
Dagmar Krenbek: Klinik Floridsdorf
Sebastien Martinez: Mount Sinai Hospital
Ricky Tsai: Mount Sinai Hospital
Jonathan Boucher: Université de Montréal
Jacob M. Berman: Mount Sinai Hospital
Katie Teng: Mount Sinai Hospital
Arshad Ayyaz: Mount Sinai Hospital
YiQing Lü: Mount Sinai Hospital
Geraldine Mbamalu: Mount Sinai Hospital
Sampath K. Loganathan: Mount Sinai Hospital
Jongbok Lee: University Health Network
Li Zhang: University Health Network
Cynthia Guidos: University Health Network
Jeffrey Wrana: Mount Sinai Hospital
Arschang Valipour: Klinik Floridsdorf
Philippe P. Roux: Université de Montréal
Jüri Reimand: University of Toronto
Hartland W. Jackson: Mount Sinai Hospital
Daniel Schramek: Mount Sinai Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract How the genetic landscape governs a tumor’s response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38841-7

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DOI: 10.1038/s41467-023-38841-7

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