Abstract 607: Inhibition of CDK4/6 and Pi3Kγ modulates mammary tumor immune microenvironment to enhance response to immunotherapy

An antitumor immune response is critical in achieving immunotherapy-driven tumor regression. Despite remarkable clinical advances in immunotherapies, patients with breast cancer have been only moderately responsive. In this study, we tested whether CDK4/6 inhibition in combination with Pi3Kγ inhibition can augment the immunotherapy response. Tumor growth was inhibited in the MMTV-PyMT breast cancer model when treated with palbociclib (CDK4/6i) in combination with anti-CD137, an antibody agonist of T cell co-stimulatory receptor 4-1BB. We also assessed the effect of palbociclib alone in a postsurgical model, where treatment began 5 days after injecting 37,000 MMTV-PyMT cells into the mammary fat pad, and show a significant inhibition of both average tumor weight and volume. In addition, we demonstrate that palbociclib can be effective in reducing total tumor burden in the PyMT-FVB spontaneous breast cancer model. Furthermore, mice treated with palbociclib in this model had an increase in CD3+ cell infiltrate in tumor lung metastasis. We used the Pi3Kγ-null mice treated with palbociclib or vehicle control to assess the effect of dual inhibition of CDK4/6 and Pi3Kγ on MMTV-PyMT tumors. We found an increase in CD45+ cells within the tumor microenvironment and an increase in MHC class II+, antigen-presenting macrophages upon palbociclib treatment. Additionally, gene expression analysis of chemokines in palbociclib-treated MCF-7 cells showed an increased expression of CCL4, CCL5, CXCL9, CXCL10, and CXCL11, each of which is implicated in T-cell tumor-homing. Overall, our results suggest that dual inhibition of CDK4/6 and Pi3Kγ may enhance tumor immunogenicity. Drugs targeting CDK4/6 and Pi3Kγ are of high clinical relevance and our findings indicate that they may be used in combination with immunotherapies for the treatment for breast cancer. Citation Format: Stacey Mont, Kevin Black, Sheau-Chiann Chen, Gregory D. Ayers, Ann Richmond, Anna E. Vilgelm. Inhibition of CDK4/6 and Pi3Kγ modulates mammary tumor immune microenvironment to enhance response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 607.