The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade

• Main Authors: David A. Schaer, Richard P. Beckmann, Jack A. Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R. Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A. Staschke, Linda A. Chung, Lacey M. Litchfield, Farhana F. Merzoug, Xueqian Gong, Philip W. Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D. Novosiadly, Michael Kalos
• Format: Article
• Language: English
• Published: Elsevier 2018-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124718302341

Summary: Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity. : Schaer, Beckmann et al. describe unique immune-modulating properties of abemaciclib that include upregulation of antigen presentation on tumor cells and increased T cell activation. These activities synergize with anti-PD-L1 therapy to further enhance immune activation, including macrophage and DC antigen presentation, and also lead to a reciprocal increase in abemaciclib-dependent cell cycle gene regulation. Keywords: CDK4/6, abemaciclib, PD-1, PD-L1, combination immunotherapy, cancer