Abstract 1634: CDK4/6 inhibition directly enhances an anti-tumor immune response in breast cancer
Authors: DeCristo* Molly J. , Goel* Shom , Watt April C. , BrinJones Haley , Sceneay Jaclyn , Li Ben , Ubellacker Jessalyn M. , Xie Shaozhen , Ramm Susanne , Kim Hye-Jung , McAllister Sandra S. , Zhao Jean J. 
Published: July 2017

The cyclin D:cyclin-dependent kinases 4 and 6 (CDK4/6) axis is one of the most frequently dysregulated pathways in human cancers, and CDK4/6 inhibitors have shown significant activity against a number of solid tumors, including breast cancer. Analogous to clinical experience, we found that the CDK4/6 inhibitor, abemaciclib, caused significant tumor regression in the MMTV-rtTA/tetO-HER2 mouse model of luminal breast cancer. However, as CDK4/6 inhibitors are known to block tumor cell proliferation, but not directly induce tumor cell apoptosis, as we confirmed in our study, the mechanisms by which CDK4/6 inhibition caused tumor regression were not clear. Notably, abemaciclib therapy increased total CD3+ T cells in these tumors, while decreasing the immunosuppressive CD4+ regulatory T cell population. Further investigation revealed that CDK4/6 inhibition directly suppresses regulatory T cells by inhibiting their proliferation without impacting natural regulatory T cell formation in the thymus, the differentiation of inducible regulatory T cells, or regulatory T cell apoptosis. We are currently exploring potential effects of CDK4/6 inhibition on regulatory T cell function and lineage stability. Analysis of CD8+ and CD4+ T cells in abemaciclib-treated tumors revealed a marked reduction in the expression of the inhibitory immune checkpoint receptors PD-1, Tim-3, CTLA-4, and LAG3. Specifically, the fraction of CD8+ T cells expressing known markers of T cell exhaustion (PD-1/Tim-3 double-positivity or high expression of PD-1) was decreased in abemaciclib-treated tumors. Importantly, antibody-mediated depletion of CD8+ T cells established that response of MMTV-rtTA/tetO-HER2 tumors to abemaciclib is dependent on CD8+ T cells. Finally, given the observed immunomodulatory effects of abemaciclib, we sought to determine if abemaciclib treatment would sensitize MMTV-rtTA/tetO-HER2 tumors to immune checkpoint blockade. Pretreatment with abemaciclib followed by combination abemaciclib and α-PDL1 significantly enhanced tumor regression compared to abemaciclib or α-PDL1 alone. Our studies reveal a novel mechanism by which CDK4/6 inhibitors directly elicit an anti-tumor immune response. These results provide strong rationale for further investigations into combining CDK4/6 inhibitors with immune checkpoint blockade in breast cancer.

Citation Format: Molly J. DeCristo*, Shom Goel*, April C. Watt, Haley BrinJones, Jaclyn Sceneay, Ben Li, Jessalyn M. Ubellacker, Shaozhen Xie, Susanne Ramm, Hye-Jung Kim, Sandra S. McAllister, Jean J. Zhao. CDK4/6 inhibition directly enhances an anti-tumor immune response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1634. doi:10.1158/1538-7445.AM2017-1634