In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer
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 reco...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38841-7 |
| _version_ | 1827710291812548608 |
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| author | 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 Daniel Schramek |
| author_facet | 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 Daniel Schramek |
| author_sort | Dzana Dervovic |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:36:58Z |
| format | Article |
| id | doaj.art-e4b4d4a5470d43e0817e0d24ed7429c7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:36:58Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e4b4d4a5470d43e0817e0d24ed7429c72023-11-20T09:51:02ZengNature PortfolioNature Communications2041-17232023-05-0114112110.1038/s41467-023-38841-7In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancerDzana Dervovic0Ahmad A. Malik1Edward L. Y. Chen2Masahiro Narimatsu3Nina Adler4Somaieh Afiuni-Zadeh5Dagmar Krenbek6Sebastien Martinez7Ricky Tsai8Jonathan Boucher9Jacob M. Berman10Katie Teng11Arshad Ayyaz12YiQing Lü13Geraldine Mbamalu14Sampath K. Loganathan15Jongbok Lee16Li Zhang17Cynthia Guidos18Jeffrey Wrana19Arschang Valipour20Philippe P. Roux21Jüri Reimand22Hartland W. Jackson23Daniel Schramek24Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalComputational Biology Program, Ontario Institute for Cancer ResearchCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalDepartment of Pathology and Bacteriology, Klinik FloridsdorfCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalInstitute for Research in Immunology and Cancer (IRIC), Université de MontréalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalToronto General Hospital Research Institute, University Health NetworkToronto General Hospital Research Institute, University Health NetworkSickKids Research Institute, University Health NetworkCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalKarl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Klinik FloridsdorfInstitute for Research in Immunology and Cancer (IRIC), Université de MontréalDepartment of Molecular Genetics, University of TorontoCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalCentre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai HospitalAbstract 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.https://doi.org/10.1038/s41467-023-38841-7 |
| spellingShingle | 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 Daniel Schramek In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer Nature Communications |
| title | In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer |
| title_full | In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer |
| title_fullStr | In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer |
| title_full_unstemmed | In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer |
| title_short | In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer |
| title_sort | in vivo crispr screens reveal serpinb9 and adam2 as regulators of immune therapy response in lung cancer |
| url | https://doi.org/10.1038/s41467-023-38841-7 |
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