Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models
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PRIMARY RESEARCH
Cancer Cell International Open Access
Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models Kyle Nolan1, Gregory Verzosa1, Tim Cleaver1, Darinee Tippimanchai1, Lisa N. DePledge2, Xiao‑Jing Wang2, Christian Young2, Anh Le3, Robert Doebele3, Howard Li1,5 and Stephen P. Malkoski1,4*
Abstract Background: Immunocompetent animal models are required to study tumor-host interactions, immunotherapy, and immunotherapeutic combinations, however the currently available immunocompetent lung cancer models have substantial limitations. While orthotopic models potentially help fill this gap, the utility of these models has been limited by the very small number of murine lung cancer cell lines capable of forming orthotopic tumors in immuno‑ competent C57BL/6 hosts. Methods: Primary lung tumors with specific genetic alterations were created in C57BL/6 background mice. These tumors were then passaged through other animals to increase tumorigenicity and select for the ability to grow in a non-self animal. Once tumors demonstrated growth in a non-self host, cell lines were established. Successful cell lines were evaluated for the ability to produce orthotopic lung tumors in immunocompetent hosts. Results: We produced six murine lung cancer lines capable of orthotopic lung tumor formation in immunocom‑ petent C57BL/6 animals. These lines demonstrate the expected genetic alterations based on their primary tumor genetics. Conclusions: These novel cell lines will be useful for evaluating tumor-host interactions, the impact of specific onco‑ genic alterations on the tumor microenvironment, and immunotherapeutic approaches. This method of generating murine lines capable of orthotopic growth can likely be applied to other tumors and will broaden the applicability of pre-clinical testing of immunotherapeutic treatment regimens. Keywords: Lung cancer, Mouse models, Orthotopic murine lung cancer models Background Although immunotherapy is the biggest treatment advance in metastatic lung cancer in over 30 years most patients do not respond to this approach and a better basic understanding of tumor-immune interactions is required for immunotherapy to reach its full *Correspondence: [email protected] 1 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, 12700 E. 19th Avenue, RC2, Room #9112, Mail stop C272, Aurora, CO 80045, USA Full list of author information is available at the end of the article
potential [1]. Unfortunately, the immunocompetent animal models required for these studies are extremely limited. While genetically engineered mouse models (GEMMs) produce tumors in an immunocompetent background, many GEMMs generate multifocal tumors of low malignant potential that may not accurately recapitulate the complex tumor-host interactions present during disease progression [2]. In addition, the low mutational burden of GEMM tumors may limit their utility for studying immunotherapy where therapeutic
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