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eSymposia | Advances in Cancer Immunotherapy


Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas


Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Description

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.

Speaker(s):

  • Jing Wang, MD, PhD, University of Colorado Anschutz Medical Campus

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