Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

التفاصيل البيبلوغرافية
العنوان: Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer
المؤلفون: Sara Moufarrij, Aneil Srivastava, Stephanie Gomez, Melissa Hadley, Erica Palmer, Paul Tran Austin, Sarah Chisholm, Noor Diab, Kyle Roche, Angela Yu, Jing Li, Wenge Zhu, Micael Lopez-Acevedo, Alejandro Villagra, Katherine B. Chiappinelli
المصدر: Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
Scientific Reports
بيانات النشر: Nature Publishing Group, 2020.
سنة النشر: 2020
مصطلحات موضوعية: medicine.medical_treatment, Antigen presentation, lcsh:Medicine, Article, 03 medical and health sciences, Ovarian tumor, 0302 clinical medicine, Immune system, Immunoediting, Interferon, Medicine, lcsh:Science, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Multidisciplinary, DNA methylation, business.industry, lcsh:R, medicine.disease, 3. Good health, Cytokine, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, lcsh:Q, business, Ovarian cancer, medicine.drug
الوصف: Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.
اللغة: English
تدمد: 2045-2322
DOI: 10.1038/s41598-020-60409-4
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::60e9746ab9e0d6cc35e0546105f2cd1e
http://link.springer.com/article/10.1038/s41598-020-60409-4
Rights: OPEN
رقم الانضمام: edsair.doi.dedup.....60e9746ab9e0d6cc35e0546105f2cd1e
قاعدة البيانات: OpenAIRE
الوصف
تدمد:20452322
DOI:10.1038/s41598-020-60409-4