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|Ref Type||Journal Article|
|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|
|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.|
|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|