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A mouse model for the study of anti-tumor T cell responses in Kras-driven lung adenocarcinoma
Brittany Fitzgerald1, Kelli A Connolly1, Can Cui1
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA.
Abstract:
Kras-driven lung adenocarcinoma (LUAD) is the most common lung cancer. A significant fraction of patients with Kras-driven LUAD respond to immunotherapy, but mechanistic studies of immune responses against LUAD have been limited because of a lack of immunotherapy-responsive models. We report the development of the immunogenic KP × NINJA (inversion inducible joined neoantigen) (KP-NINJA) LUAD model. This model allows temporal uncoupling of antigen and tumor induction, which allows one to wait until after infection-induced inflammation has subsided to induce neoantigen expression by tumors. Neoantigen expression is restricted to EPCAM+ cells in the lung and expression of neoantigen was more consistent between tumors than when neoantigens were encoded on lentiviruses. Moreover, tumors were infiltrated by tumor-specific CD8 T cells. Finally, LUAD cell lines derived from KP-NINJA mice were immunogenic and responded to immune checkpoint therapy (anti-PD1 and anti-CTLA4), providing means for future studies into the immunobiology of therapeutic responses in LUAD.
Insights
Researchers developed a novel mouse model for Kras-driven lung adenocarcinoma (LUAD) that is responsive to immunotherapy. This new model aids in studying immune responses and therapeutic strategies for lung cancer.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Kras-driven lung adenocarcinoma (LUAD) is a prevalent cancer.
- Limited models exist for studying immune responses and immunotherapy in LUAD.
- Understanding immune interactions is crucial for developing effective LUAD treatments.
Purpose of the Study:
- To develop a novel, immunogenic mouse model for Kras-driven LUAD.
- To enable mechanistic studies of immune responses against LUAD.
- To facilitate research into immunotherapy efficacy in LUAD.
Main Methods:
- Development of the KP × NINJA (KP-NINJA) LUAD model.
- Temporal uncoupling of antigen and tumor induction.
- Neoantigen expression restricted to EPCAM+ lung cells.
- Derivation of LUAD cell lines from the KP-NINJA model.
Main Results:
- The KP-NINJA model allows controlled neoantigen expression.
- Neoantigen expression was consistent and tumor-specific.
- Tumors showed infiltration by CD8 T cells.
- Derived LUAD cell lines were immunogenic and responded to anti-PD1/anti-CTLA4 therapy.
Conclusions:
- The KP-NINJA model provides a valuable tool for LUAD immunotherapy research.
- This model facilitates studies on the immunobiology of therapeutic responses in LUAD.
- It opens new avenues for investigating novel lung cancer treatment strategies.
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