LAUSR

Brain metastasis (BrM) incidence is rising due to longer survival resulted from better systemic control of cancer, counting for approximately 20% of patients with cancers. Major cancer types, including lung, breast, and skin cancers, have a high rate to develop BrM with a 1-year survival rate of less than 20% for symptomatic patients. The overall response rate for immune checkpoint inhibitors (ICI) is merely 10-30% in patients with neurological symptoms. Developing novel combinatorial therapeutic strategies based on mechanistic understanding is urgently needed to further improve the efficacy of current immunotherapies in BrM patients. We recently found that BrMs in patients frequently have severe MHC-I loss. BrM patients' scRNA-seq data from available datasets show that MHC-I expression level is negatively correlated with HDAC level in breast cancer brain metastasis. On the other hand, HDAC inhibitors (HDACi) are epigenetic modulators which have been indicated to recover MHC-I expression loss that contributes to immune invasion. HDACi has been indicated to enhance ICI efficacy in primary tumors by reprogramming the tumor microenvironment (TME). However, the immunomodulatory effect of HDACi is unclear in the unique brain immune microenvironment (BrIME), which is characterized as immunosuppressive. Here, we report that although the selective-HDACi Entinostat has a relatively poor blood-brain barrier (BBB) penetration compared to pan-HDACi Panobinostat, Entinostat induced a comparable level of histone acetylation in the brain to that of Panobinostat. Furthermore, combinatorial treatment consisting of HDACi Entinostat/Panobinostat and anti-PD1 reduced BrM outgrowth of EO771 mammary tumor cell-induced BrM in synergetic mouse model. We explored the impact of HDACi on cell surface MHC-I expression by flow cytometry. Entinostat restored MHC-I expression levels on both brain-seeking human and murine breast and lung cancer cell lines, indicating a general epigenetic regulation on MHC-I expression by inhibition of HDACs. To dissect the impact of HDACi on the BrIME, immune profiling of BrM was performed by mass cytometry (CyTOF). Notably, Entinostat induced a dramatic increment of a specific antigen-presenting cell (APC) cluster in BrM-bearing BrIME with increased ratio of M1 proinflammatory macrophages: M2 tumor-associated macrophages (TAMs) and decreased Tregs. Our results suggest that Entinostat can upregulate MHC-I for more effective antigen presentation and enhance anti-tumor immunity in BrIME. Citation Format: Shao-Ping Yang, Yimin Duan, Xiangliang Yuan, Lin Zhang, Patrick Zhang, Dihua Yu. Selective-HDAC inhibitor relieves the suppressive immune microenvironment in the brain to impede breast cancer brain metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6427.