Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas Xiaoguang Wang1, Brittany C.Waschke1, Rachel A.Woolaver1, Zhangguo Chen1, Gan Zhang2, Anthony D. Piscopio3, Xuedong Liu2,3, and Jing H.Wang1,* 1Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. 2Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado. 3OnKure Inc., Boulder, Colorado. *Correspondence author 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 immunological effects of HDACi on anti-tumor 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.
University of Colorado Anschutz Medical Campus
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