PD1 blockade is effective in a subset of B-cell lymphoma patients (e.g., classical Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To overcome PD1 resistance, we employ a newly developed isoform-selective histone-deacetylase-inhibitor (HDACi) (OKI-179) and a novel mouse mature B-cell lymphoma, G1XP lymphoma, that resembles immunosuppressive features of human B-cell lymphomas including downregulation of major histocompatibility complex (MHC) class I and II, exhaustion of CD8 and CD4 tumor-infiltrating lymphocytes (TILs), and PD1-blockade resistance. Using multiple lymphoma models, we show that combined treatment of OKI-179/anti-PD1 significantly inhibited growth of B-cell lymphomas refractory to PD1 blockade; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated to MHC class II level. We conclude that OKI-179 sensitizes lymphomas to PD1 blockade by enhancing tumor immunogenicity. Additionally, we found that different HDACi exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Thus, our study highlights the importance of immunologic effects of HDACi on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and unique profiles of HDACi.
Citation Format: Xiaoguang Wang, Brittany C. Waschke, Rachel A. Woolaver, Zhangguo Chen, Gan Zhang, Anthony D. Piscopio, Xuedong Liu, Jing H. Wang. Mechanistic consequences of histone-deacetylase inhibition towards sensitizing PD1 blockade-resistant B-cell lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-54.