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CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Naema Nayyar1,2, Magali A de Sauvage2, Jane Chuprin1
1Program in Molecular Medicine, UMass Chan Medical School, Worcester, Massachusetts.
Purpose:
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis.
Experimental Design:
Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor-immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development.
Results:
We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells.
Conclusions:
Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases. See related commentary by Margolin, p. 257.
Insights
Combining a CDK4/6 inhibitor (CDKi) with PD-1 inhibition effectively reduced brain tumor burden and improved survival in mouse models. This combination therapy modulated the tumor-immune microenvironment, enhancing anti-tumor T-cell responses.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Brain metastases present significant clinical challenges due to high morbidity and resistance to therapies like immune checkpoint inhibitors.
- Understanding the tumor-immune microenvironment (TIME) is crucial for developing effective treatments for brain metastases.
Purpose of the Study:
- To investigate if the CDK4/6 inhibitor (CDKi) abemaciclib can enhance the efficacy of programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis.
- To evaluate the impact of combined CDKi and PD-1 inhibition on intracranial and extracranial tumor burden and the tumor-immune microenvironment.
Main Methods:
- Utilized immunocompetent mouse models of brain metastasis with concurrent intracranial and extracranial tumors.
- Assessed treatment response in vivo and analyzed the tumor-immune microenvironment (TIME) using immunofluorescence, multiplex immunoassays, and flow cytometry.
- Investigated the effect of CDKi on human T-cell development in humanized immune system mouse models.
Main Results:
- Combination therapy with abemaciclib and PD-1 inhibition significantly reduced tumor burden and improved overall survival in mice.
- The treatment altered the TIME in an organ-specific manner, increasing CD8+ effector T-cell subsets and depleting CD4+ regulatory T (Treg) cells within intracranial tumors.
- Abemaciclib treatment promoted CD8+ T-cell development and maintenance while reducing Treg cells in humanized mouse models.
Conclusions:
- The combination of CDK4/6 and PD-1 inhibition demonstrates therapeutic potential for brain metastases.
- Distinct properties of intracranial versus extracranial tumors necessitate organ-specific treatment considerations.
- Clinical investigation of this combination therapy in patients with brain metastases is warranted.
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