Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas
| Autor: | Brittany C. Waschke, Rachel A. Woolaver, Jing Wang, Anthony D. Piscopio, Xuedong Liu, Gan Zhang, Xiaoguang Wang, Zhangguo Chen |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Lymphoma B-Cell medicine.drug_class Programmed Cell Death 1 Receptor Immunology Article 03 medical and health sciences Antineoplastic Agents Immunological Lymphocytes Tumor-Infiltrating 0302 clinical medicine Cell Line Tumor hemic and lymphatic diseases MHC class I medicine Humans Gene Knock-In Techniques B cell MHC class II biology business.industry Histocompatibility Antigens Class I Histone deacetylase inhibitor Drug Synergism medicine.disease Lymphoma Blockade Histone Deacetylase Inhibitors medicine.anatomical_structure Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research biology.protein Histone deacetylase business CD8 030215 immunology |
| Zdroj: | Cancer Immunology Research. 7:1318-1331 |
| ISSN: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-18-0875 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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