The antitumor effects of entinostat in ovarian cancer require adaptive immunity

Autor: Lyse A. Norian, J. Michael Straughn, Selene Meza-Perez, Troy D. Randall, Donald J. Buchsbaum, Eddy S. Yang, Haller J. Smith, Andres Forero, Tyler R. McCaw, Ashwini A. Katre, Angelina I. Londono, Rebecca C. Arend
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Cell Survival
Pyridines
medicine.drug_class
chemical and pharmacologic phenomena
Adaptive Immunity
Flow cytometry
Immunocompromised Host
Mice
Random Allocation
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Immune system
Cell Line
Tumor
CIITA
Animals
Humans
Medicine
Precision Medicine
Cell Proliferation
Ovarian Neoplasms
biology
medicine.diagnostic_test
Entinostat
business.industry
Histone deacetylase inhibitor
Histocompatibility Antigens Class II
Nuclear Proteins
Acquired immune system
medicine.disease
Xenograft Model Antitumor Assays
Up-Regulation
Gene Expression Regulation
Neoplastic
Histone Deacetylase Inhibitors
Mice
Inbred C57BL
030104 developmental biology
Oncology
chemistry
Granzyme
030220 oncology & carcinogenesis
Benzamides
Trans-Activators
Cancer research
biology.protein
Female
business
Ovarian cancer
Zdroj: Cancer. 124:4657-4666
ISSN: 1097-0142
0008-543X
DOI: 10.1002/cncr.31761
Popis: Background Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in patients with ovarian cancer. The authors previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian cancer cells. In the current study, they evaluated whether entinostat treatment and resultant MHCII expression would enhance beneficial immune responses and impair tumor growth in mice with ovarian cancer. Methods C57BL/6 mice bearing intraperitoneal ID8 tumors were randomized to receive entinostat 20 mg/kg daily versus control. Changes in messenger RNA (mRNA) expression of 46 genes important for antitumor immunity were evaluated using NanoString analysis, and multicolor flow cytometry was used to measure changes in protein expression and tumor-infiltrating immune cells. Results Entinostat treatment decreased the growth of both subcutaneously and omental ID8 tumors and prolonged survival in immunocompetent C57BL/6 mice. NanoString analysis revealed significant changes in mRNA expression in 21 of 46 genes, including increased expression of the MHCI pathway, the MHCII transactivator (CIITA), interferon γ, and granzyme B. C57BL/6 mice that received entinostat had increased MHCII expression on omental tumor cells and a higher frequency of tumor-infiltrating, CD8-positive T cells by flow cytometry. In immunocompromised mice, treatment with entinostat had no effect on tumor size and did not increase MHCII expression. Conclusions In the current murine ovarian cancer model, entinostat treatment enhances beneficial immune responses. Moreover, these antitumor effects of entinostat are dependent on an intact immune system. Future studies combining entinostat with checkpoint inhibitors or other immunomodulatory agents may achieve more durable antitumor responses in patients with ovarian cancer.
Databáze: OpenAIRE
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