PMID- 32209571 OWN - NLM STAT- MEDLINE DCOM- 20210914 LR - 20240214 IS - 1557-3265 (Electronic) IS - 1078-0432 (Print) IS - 1078-0432 (Linking) VI - 26 IP - 13 DP - 2020 Jul 1 TI - Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy. PG - 3431-3442 LID - 10.1158/1078-0432.CCR-19-1627 [doi] AB - PURPOSE: Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed. EXPERIMENTAL DESIGN: We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines. RESULTS: We show that multiplex gene editing of mouse lung organoids using the CRISPR-Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell-mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti-PD-1 therapy. CONCLUSIONS: We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage-inducing therapies in the treatment of LSCC. CI - (c)2020 American Association for Cancer Research. FAU - Hai, Josephine AU - Hai J AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kwok-kin.wong@nyumc.org Adam_Bass@dfci.harvard.edu josephine.hai@mail.utoronto.ca. FAU - Zhang, Hua AU - Zhang H AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Zhou, Jin AU - Zhou J AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Wu, Zhong AU - Wu Z AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Chen, Ting AU - Chen T AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Papadopoulos, Eleni AU - Papadopoulos E AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Dowling, Catriona M AU - Dowling CM AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Pyon, Val AU - Pyon V AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Pan, Yuanwang AU - Pan Y AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Liu, Jie Bin AU - Liu JB AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Bronson, Roderick T AU - Bronson RT AD - Rodent Histopathology, Harvard Medical School, Boston, Massachusetts. FAU - Silver, Heather AU - Silver H AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Lizotte, Patrick H AU - Lizotte PH AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. AD - Belfer Center for Applied Cancer Science, Boston, Massachusetts. FAU - Deng, Jiehui AU - Deng J AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Campbell, Joshua D AU - Campbell JD AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. AD - Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. FAU - Sholl, Lynette M AU - Sholl LM AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. FAU - Ng, Christine AU - Ng C AD - Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. FAU - Tsao, Ming-Sound AU - Tsao MS AD - Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. FAU - Thakurdin, Cassandra AU - Thakurdin C AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. FAU - Bass, Adam J AU - Bass AJ AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kwok-kin.wong@nyumc.org Adam_Bass@dfci.harvard.edu josephine.hai@mail.utoronto.ca. FAU - Wong, Kwok-Kin AU - Wong KK AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kwok-kin.wong@nyumc.org Adam_Bass@dfci.harvard.edu josephine.hai@mail.utoronto.ca. AD - Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. LA - eng GR - R01 CA216188/CA/NCI NIH HHS/United States GR - R01 CA219670/CA/NCI NIH HHS/United States GR - R01 CA166480/CA/NCI NIH HHS/United States GR - P01 CA098101/CA/NCI NIH HHS/United States GR - R01 CA201049/CA/NCI NIH HHS/United States GR - R01 CA197329/CA/NCI NIH HHS/United States GR - U01 CA213333/CA/NCI NIH HHS/United States GR - R01 CA205150/CA/NCI NIH HHS/United States GR - R01 CA187119/CA/NCI NIH HHS/United States GR - R01 CA196932/CA/NCI NIH HHS/United States GR - P01 CA154303/CA/NCI NIH HHS/United States GR - U01 CA233084/CA/NCI NIH HHS/United States GR - R01 CA140594/CA/NCI NIH HHS/United States GR - R01 CA222218/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20200324 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Biomarkers) RN - 0 (Biomarkers, Tumor) SB - IM MH - Animals MH - Biomarkers MH - Biomarkers, Tumor MH - Carcinoma, Squamous Cell/drug therapy/metabolism/*pathology MH - Cell Line, Tumor MH - Combined Modality Therapy MH - *Disease Models, Animal MH - Gene Editing MH - Gene Expression MH - Genetic Engineering MH - Humans MH - Immunohistochemistry MH - Immunotherapy MH - Lung/*drug effects/*pathology MH - Lung Neoplasms/drug therapy/metabolism/*pathology MH - Lymphocytes, Tumor-Infiltrating/immunology/metabolism/pathology MH - Mice MH - *Mice, Transgenic MH - Organoids/*drug effects MH - Xenograft Model Antitumor Assays PMC - PMC7334092 MID - NIHMS1579665 EDAT- 2020/03/27 06:00 MHDA- 2021/09/15 06:00 PMCR- 2021/01/01 CRDT- 2020/03/27 06:00 PHST- 2019/05/17 00:00 [received] PHST- 2019/11/22 00:00 [revised] PHST- 2020/03/19 00:00 [accepted] PHST- 2020/03/27 06:00 [pubmed] PHST- 2021/09/15 06:00 [medline] PHST- 2020/03/27 06:00 [entrez] PHST- 2021/01/01 00:00 [pmc-release] AID - 1078-0432.CCR-19-1627 [pii] AID - 10.1158/1078-0432.CCR-19-1627 [doi] PST - ppublish SO - Clin Cancer Res. 2020 Jul 1;26(13):3431-3442. doi: 10.1158/1078-0432.CCR-19-1627. Epub 2020 Mar 24.