Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model.

Abstract

The lack of second-line treatment for relapsed ovarian cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian cancer model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8(+) T cells, promotes their production of IFNγ and TNFα, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this model, the efficacy of anti-CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naïve T cells into effector T cells and prolongs cytotoxic lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian cancer.

• Authors: Lei Wang, Zohreh Amoozgar, Jing Huang, Mohammad H Saleh, Deyin Xing, Sandra Orsulic, Michael S Goldberg
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 3 Issue 9 Pg. 1030-41 (Sep 2015) ISSN: 2326-6074 [Electronic] United States
• PMID: 26056145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• CTLA-4 Antigen
• Cytokines
• Decitabine
• Azacitidine

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Ascitic Fluid (immunology)
• Azacitidine (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• CD8-Positive T-Lymphocytes (immunology)
• CTLA-4 Antigen (antagonists & inhibitors)
• Cell Movement (drug effects)
• Cell Transformation, Neoplastic (drug effects, immunology)
• Cytokines (biosynthesis)
• Decitabine
• Female
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Humans
• Immunotherapy (methods)
• Killer Cells, Natural (drug effects, immunology)
• Lymph Nodes (immunology)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Mice
• Ovarian Neoplasms (drug therapy, immunology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays (methods)