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Ref Type Journal Article
PMID (31235619)
Authors Wang X, Waschke BC, Woolaver RA, Chen Z, Zhang G, Piscopio AD, Liu X, Wang JH
Title Histone Deacetylase Inhibition Sensitizes PD1 Blockade-Resistant B-cell Lymphomas.
Journal Cancer immunology research
Vol 7
Issue 8
Date 2019 Aug
URL
Abstract Text PD1 blockade is effective in a subset of patients with B-cell lymphoma (e.g., classical-Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To study PD1 resistance, we used an isoform-selective histone deacetylase inhibitor (HDACi; OKI-179), and a mouse mature B-cell lymphoma, G1XP lymphoma, immunosuppressive features of which resemble those of human B-cell lymphomas, including downregulation of MHC class I and II, exhaustion of CD8+ and CD4+ tumor-infiltrating lymphocytes (TIL), and PD1-blockade resistance. Using two lymphoma models, we show that treatment of B-cell lymphomas refractory to PD1 blockade with both OKI-179 and anti-PD1 inhibited growth; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated with MHC class II expression level. We conclude that OKI-179 sensitizes lymphomas to PD1-blockade by enhancing tumor immunogenicity. In addition, we found that different HDACis exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Our study highlights the immunologic effects of HDACis on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and the individual profiles of HDACi.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
OKI-005 HDAC Inhibitor 38 OKI-005 inhibits histone-deacetylase, which may lead to enhanced tumor immunogenicity and sensitize tumor cells to immunotherapy (PMID: 31235619).
OKI-179 HDAC Inhibitor 38 OKI-179 is a small molecule that inhibits Class I, IIb, and IV histone deacetylases, which may result in reduced tumor growth (PMID: 31235619).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lymphoma not applicable OKI-179 + unspecified PD-1 antibody Preclinical - Cell line xenograft Actionable In a preclinical study, OKI-179 upregulated MHC expression, sensitized lymphoma cells to anti-PD-1 treatment in cell line xenograft models (PMID: 31235619). 31235619
Unknown unknown lymphoma not applicable OKI-179 Preclinical - Cell culture Actionable In a preclinical study, OKI-005 induced cell cycle arrest and apoptosis in lymphoma cells in culture (PMID: 31235619). 31235619
Unknown unknown lymphoma not applicable OKI-005 Preclinical - Cell culture Actionable In a preclinical study, OKI-005 induced cell cycle arrest and apoptosis in lymphoma cells in culture (PMID: 31235619). 31235619