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Published on: June 28, 2018
Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study
Josephine Hai1, Hua Zhang2,3, Jin Zhou2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kwok-kin.wong@nyumc.org Adam_Bass@dfci.harvard.edu josephine.hai@mail.utoronto.ca.
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.
Insights
Developing new lung squamous cell carcinoma (LSCC) mouse models using CRISPR gene editing, this study shows WEE1 inhibition combined with PD-1 blockade enhances anti-tumor immunity and improves treatment efficacy in LSCC.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Lung squamous cell carcinoma (LSCC) presents a significant clinical challenge, with limited response rates to immune checkpoint blockade (ICB) therapy.
- The development of accurate preclinical models that mirror human LSCC's genetic complexity is crucial for advancing treatment strategies.
Purpose of the Study:
- To establish a genetically precise mouse model for LSCC using CRISPR genome editing.
- To investigate the therapeutic and immunologic effects of combining WEE1 inhibition with PD-1 blockade in LSCC.
Main Methods:
- CRISPR-Cas9 genome editing was employed to delete tumor suppressors in mouse lung organoids.
- The efficacy of combination therapy (PD-1 blockade and WEE1 inhibition) was evaluated in genetically engineered mouse models and patient-derived LSCC cell lines.
Main Results:
- Multiplex gene editing efficiently generated LSCC models that recapitulate human disease genomics and phenotypes.
- WEE1 inhibition induced DNA damage, enhancing type I IFN signaling and antigen presentation in LSCC cells.
- Combination therapy promoted cytotoxic T-cell activity, reduced tumor-infiltrating neutrophils, and improved anti-tumor immune responses.
Conclusions:
- A novel LSCC mouse model was developed, facilitating the study of novel therapeutic combinations.
- Combining ICB with DNA damage-inducing agents like WEE1 inhibitors presents a promising clinical strategy for LSCC treatment.
