CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis

Authors

Naema Nayyar
Magali A de Sauvage
Jane Chuprin
Emily M Sullivan
Mohini Singh
Consuelo Torrini
Britney S Zhang
Sushobhana Bandyopadhyay
Keith A Daniels
Christopher Alvarez-Breckenridge
Ashish Dahal
Michael A Brehm
Priscilla K Brastianos

Publication Date

1-17-2024

Journal

Clinical Cancer Research

Abstract

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.

Keywords

Humans, Mice, Animals, Programmed Cell Death 1 Receptor, Brain Neoplasms, Aminopyridines, Benzimidazoles, CD8-Positive T-Lymphocytes, Tumor Microenvironment, Cyclin-Dependent Kinase 4

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Supplementary Materials

PMID: 37611074