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

Autor:	Wang X; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado., Waschke BC; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado., Woolaver RA; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado., Chen Z; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado., Zhang G; Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado., Piscopio AD; OnKure Inc., Boulder, Colorado., Liu X; Department of Biochemistry, University of Colorado Boulder, Boulder, Colorado.; OnKure Inc., Boulder, Colorado., Wang JH; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. jing.wang@ucdenver.edu.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2019 Aug; Vol. 7 (8), pp. 1318-1331. Date of Electronic Publication: 2019 Jun 24.
DOI:	10.1158/2326-6066.CIR-18-0875
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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