Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models

Nolan, Kyle; Verzosa, Gregory; Cleaver, Tim; Tippimanchai, D.; DePledge, Lisa; Wang, Xiaojing; Young, Christian D.; Le, Anh‐Tuan; Li, Howard; Malkoski, Stephen P.

doi:10.1186/s12935-020-01503-5

Cited by 18 publications

(17 citation statements)

References 40 publications

(57 reference statements)

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“…EA1 and EA3 cells were developed at the University of Colorado Anschutz Medical Center and EA1 cells have previously been described by our group (15,16). The EML4-ALK cell line referred to herein as EA2 was generously provided by Dr. Andrea Ventura at Memorial Sloan Kettering Cancer Center (17).…”

Section: Methodsmentioning

confidence: 99%

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Adaptive immunity is required for durable responses to alectinib in murine models of EML4-ALK lung cancer

Kleczko

Hinz

Nguyen

et al. 2022

Preprint

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PPurpose: Lung cancers bearing oncogenic EML4-ALK fusions respond to targeted tyrosine kinase inhibitors (TKIs; e.g. alectinib), with variation in the degree of shrinkage and duration of treatment (DOT). We previously demonstrated a positive association of a TKI-induced interferon gamma (IFNgamma) transcriptional response with DOT in EGFR-mutant lung cancers. Herein, we used murine models of EML4-ALK lung cancer to test a role for host immunity in the therapeutic response to alectinib. Experimental Design: Three murine EML4-ALK cell lines (EA1, EA2, EA3) were implanted orthotopically into the lungs of immunocompetent and immunodeficient mice and treated with alectinib. Tumor volumes were serially measured by micro CT. Immune cell content was measured by flow cytometry, multispectral immunofluorescence and CyTOF. Transcriptional responses to alectinib were assessed by RNAseq and secreted chemokines were measured by ELISA. Results: All cell lines were sensitive to alectinib in vitro. EA1 and EA3 tumors retained residual disease that rapidly progressed upon termination of treatment while EA2 tumors were eliminated by TKI treatment. Alectinib induced inflammatory transcriptional programs and multiple chemokines in all cell lines while untreated tumors exhibited distinct baseline chemokine expression patterns and content of CD8+ T cells and myeloid subsets. When propagated in immune-deficient mice, all three cell line-derived lung tumor models exhibited significant shrinkage followed by prompt progression despite continuous alectinib treatment. Conclusions: The findings support an hypothesis that host and TKI-stimulated production of chemokines by tumor cells promotes functional engagement of adaptive immune cells within the tumor microenvironment that enhances the durability and depth of TKI response.

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Section: Methodsmentioning

confidence: 99%

“…the University of Colorado Anschutz Medical Center and EA1 cells have previously been described by our group (15,16). The EML4-ALK cell line referred to herein as EA2 was generously provided by Dr.…”

Section: Establishment and Culture Of Murine Eml4-alk Cell Lines: Ea1...mentioning

confidence: 99%

Adaptive immunity is required for durable responses to alectinib in murine models of EML4-ALK lung cancer

Kleczko

Hinz

Nguyen

et al. 2022

Preprint

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“…(b) Syngeneic murine models These immunocompetent models turned out to be essential for understanding both tumor-host interactions and immune mechanisms [26]. Unfortunately, there is still a limited panel of murine lung cancer cell lines that can spontaneously form tumors in immunocompetent mice [27]. The development and validation of relevant immunocompetent syngeneic models for lung cancer will be a long process.…”

Section: Murine Models For In Vivo Studiesmentioning

confidence: 99%

Patient-Derived Lung Tumoroids—An Emerging Technology in Drug Development and Precision Medicine

et al. 2022

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Synthetic 3D multicellular systems derived from patient tumors, or tumoroids, have been developed to complete the cancer research arsenal and overcome the limits of current preclinical models. They aim to represent the molecular and structural heterogeneity of the tumor micro-environment, and its complex network of interactions, with greater accuracy. They are more predictive of clinical outcomes, of adverse events, and of resistance mechanisms. Thus, they increase the success rate of drug development, and help clinicians in their decision-making process. Lung cancer remains amongst the deadliest of diseases, and still requires intensive research. In this review, we analyze the merits and drawbacks of the current preclinical models used in lung cancer research, and the position of tumoroids. The introduction of immune cells and healthy regulatory cells in autologous tumoroid models has enabled their application to most recent therapeutic concepts. The possibility of deriving tumoroids from primary tumors within reasonable time has opened a direct approach to patient-specific features, supporting their future role in precision medicine.

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“…Recently, some GEMM-derived cell lines have emerged, such as KRASG12D p53−/−, forming lung tumors after intravenous injection, but also giving rise to a metastatic model. In 2020, Nolan et al [ 78 ] were able to develop six new lines capable of forming orthotopic tumors in 75% of recipient C57BL/6 host lungs. While those lines will need further validation, such initiatives are very much needed.…”

Section: In Vitro Modelsmentioning

confidence: 99%

How to Improve SBRT Outcomes in NSCLC: From Pre-Clinical Modeling to Successful Clinical Translation

Milić

Mondini

Deutsch

2022

Cancers

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Despite major research and clinical efforts, lung cancer remains the leading cause of cancer-related death. While the delivery of conformal radiotherapy and image guidance of stereotactic body radiotherapy (SBRT) have revolutionized the treatment of early-stage non-small-cell lung cancer (NSCLC), additional research is needed to elucidate underlying mechanisms of resistance and identify novel therapeutic combinations. Clinical progress relies on the successful translation of pre-clinical work, which so far has not always yielded expected results. Improved clinical modelling involves characterizing the preclinical models and selecting appropriate experimental designs that faithfully mimic precise clinical scenarios. Here, we review the current role of SBRT and the scope of pre-clinical armamentarium at our disposal to improve successful clinical translation of pre-clinical research in the radiation oncology of NSCLC.

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Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models

Cited by 18 publications

References 40 publications

Adaptive immunity is required for durable responses to alectinib in murine models of EML4-ALK lung cancer

Adaptive immunity is required for durable responses to alectinib in murine models of EML4-ALK lung cancer

Patient-Derived Lung Tumoroids—An Emerging Technology in Drug Development and Precision Medicine

How to Improve SBRT Outcomes in NSCLC: From Pre-Clinical Modeling to Successful Clinical Translation

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