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

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.

Genome wide transcription profiling reveals a major role for the transcription factor Atf1 in regulation of cell division in Schizosaccharomyces pombe.

The mechanism underlying stringently controlled sequence of events in the eukaryotic cell cycle involves periodic transcription of a number of genes encoding important regulators of cell cycle, growth, proliferation and apoptosis. Deregulated activities of transcription factors that contribute to this programmed gene expression, are associated with many diseases including cancer. A detailed mechanistic understanding of the transcriptional control associated with cell division is, therefore, important. We have reported earlier that the transcription factor Atf1 in Schizosaccharomyces pombe can regulate G2-M transition by directly controlling the expression of the mitotic cyclin Cdc13 (1).To gain a better understanding of the role of Atf1 in cell cycle, we performed a microarray based identification of cell cycle related targets of Atf1. The microarray data are available at NCBI's Gene Expression Omnibus (GEO) Series (accession number GSE71820). Here we report the annotation of the genes whose expression get altered by Atf1 overexpression and also provide details related to sample processing and statistical analysis of our microarray data.