Abstract 4176: Histone deacetylase inhibitor Panobinostat enhances efficacy of immune checkpoint inhibitor via upregulating antigen presentation in breast cancer brain metastasis

Abstract

Abstract Brain metastasis (BrM) affects millions of cancer patients and major cancer types, e.g., lung cancer, melanoma, and breast cancer, have high incidences of BrM. Symptomatic BrM patients have a less than 20% 1-year survival rate. The poor clinical outcome is due to lack of effective treatment for BrM as even immune checkpoint inhibition (ICI) only showed effects in 55% asymptomatic BrM in melanoma patients. Novel effective combination therapies are urgently needed to address metastasis in the unique brain immune microenvironment (BrIME). Interestingly, our RNA-seq data of patients treated at MD Anderson Cancer Center and immunohistochemistry (IHC) analysis of tumors of various mouse models showed that BrM express significantly lower major histocompatibility class I (MHC-I) and higher histone deacetylase (HDAC) 1 compares to extracranial tumors or metastasis. HDAC inhibitors (HDACi) have been reported to upregulate MHC-I in extracranial tumors. In this study, we tested whether HDACi, Panobinostat, can upregulate MHC-I expression in BrM and whether Panobinostat combined with ICI (e.g., anti-PD1) treatment in mouse models can impede BrM development. Clearly, our data showed that HDACi Panobinostat significantly increased MHC-I expression in brain-seeking human breast cancer cells (MDA-231, MDA-435) and mouse mammary tumor cells (4T1, EO771) with or without IFN-γ treatment. We then tested Panobinostat penetration of the blood-brain barrier (BBB) for treating BrM in vivo. C57BL/6 mice were treated with either 10 or 20mpk (i.p.) Panobinostat for three consecutive days. Mass spectrum analysis shows that Panobinostat can be detected in the brain at level of 10-8M after the treatment. We found that Panobinostat treatment increased both CD4+ and CD8+ T cell in the brain by FACS analysis. To test therapeutic efficacy of HDACi and ICI combination therapy in BrM, we induced BrM in C57BL/6 mice by intracarotid artery (ICA) injection of E0771-Luc.GFP tumor cells, then mice were divided to four groups and were treated with i) vehicle, ii) Panobinostat, iii) anti-PD1 and iv) Panobinostat +anti-PD1. We found that combination of Panobinostat with anti-PD1 more effectively inhibited BrM tumor outgrowth compares to either monotherapy and the vehicle control. Furthermore, Immunohistochemistry staining revealed upregulated MHC-I in BrM tumor cells and increased CD8+ T cell infiltration by Panobinostat treatment. In summary, our data indicated that HDACi Panobinostat can increase ICI efficacy in BrM by upregulating MHC-I for enhanced antigen presentation. Citation Format: Shao-Ping Yang, Yimin Duan, Xiangliang Yuan, Lin Zhang, Patrick Zhang, Jason T. Huse, Dihua Yu. Histone deacetylase inhibitor Panobinostat enhances efficacy of immune checkpoint inhibitor via upregulating antigen presentation in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4176.