The purpose of our study is to investigate the immunologic effects of CDK4/6 inhibitors in triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype for which there are no targeted therapies. CDK4/6 inhibitors, including the recently FDA approved abemaciclib, show promising response rates in patients with advanced stage hormone receptor-positive (HR+) breast cancer. Our previous report established that CDK4/6 inhibitors promote antitumor immunity by inducing tumor cell antigen presentation by activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature 2017). In addition, CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T-cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose Rb protein expression, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, reports show around 50%-70% TNBC still has intact RB. We found murine and human TNBC cell lines that express Rb to varying extents and decrease proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, since a recent trial evaluating αPD-L1 therapy (atezolizumab) reported enhanced progression-free survival in patients with PD-L1+ tumors. These data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of TNBC, as we previously reported in our Her2+ model. Abemaciclib also increased total CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naive CD8+ and CD4+ T cells increased with abemaciclib treatment in the spleen, suggesting a favorable antitumor systemic immunologic effect. CDK4/6 inhibitors might therefore show efficacy in treating TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naive T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype.
Citation Format: Qiuchen Guo, Gregory J. Goreczny, Adam Maynard, Milos Spasic, Sandra S. McAllister. Investigating CDK4/6 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A18.