期刊
CANCER IMMUNOLOGY RESEARCH
卷 6, 期 12, 页码 1561-1577出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0070
关键词
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资金
- NIH [RO1CA184926]
- Stand Up 2 Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant [SU2C-AACR-DT14-14]
- NIH/NCI [P50CA062924]
- Lustgarten Foundation's Research Investigator's Award Program
- Broccoli Foundation
- Bloombergsimilar toKimmel Institute for Cancer Immunotherapy
- Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care
- Commonwealth Foundation for Cancer Research
- MacMillan Pathway to Independence Fellowship [5T32 CA009071-34]
- NATIONAL CANCER INSTITUTE [T32CA009071, R01CA184926, P50CA062924] Funding Source: NIH RePORTER
Immune-checkpoint inhibition (ICI) has revolutionized treatment in cancers that are naturally immunogenic by enabling infiltration of T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. Tumors possessing complex immunosuppressive TMEs such as breast and pancreatic cancers present unique therapeutic obstacles as response rates to ICI remain low. Such tumors often recruit myeloid-derived suppressor cells (MDSCs), whose functioning prohibits both T-cell activation and infiltration. We attempted to sensitize these tumors to ICI using epigenetic modulation to target MDSC trafficking and function to foster a less immunosuppressive TME. We showed that combining a histone deacetylase inhibitor, entinostat (ENT), with anti-PD-1, anti-CTLA-4, or both significantly improved tumor-free survival in both the HER2/neu transgenic breast cancer and the Panc02 metastatic pancreatic can-cer mouse models. Using flow cytometry, gene-expression profiling, and ex vivo functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) andMDSCs, as well as their functional capabilities. Weshowed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic MDSCs in the TME of both tumor types. Wealso demonstrated an increase in activated granzymeB- producing CD8 thorn T effector cells in mice treated with combination therapy. Gene-expression profiling of both MDSCs and TILs identified significant changes in immune-related pathways. In summary, addition of ENT to ICI significantly altered infiltration and function of innate immune cells, allowing for a more robust adaptive immune response. These findings provide a rationale for combination therapy in patients with immune-resistant tumors, including breast and pancreatic cancers. (C) 2018 AACR.
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