Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs

Brian J. Christmas, Christine I. Rafie, Alexander C. Hopkins, Blake A. Scott, Hayley S. Ma, Kayla A. Cruz, Skylar Woolman, Todd D Armstrong, Roisin Connolly, Nilofer Azad, Elizabeth Jaffee, Evanthia Roussos Torres

Research output: Contribution to journalArticle

Abstract

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 cancer mouse models. Using flow cytometry, gene-expression profiling, and ex vivo functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) and MDSCs, as well as their functional capabilities. We showed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic MDSCs in the TME of both tumor types. We also demonstrated an increase in activated granzyme-B–producing CD8þ 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.

Original languageEnglish (US)
Pages (from-to)1561-1577
Number of pages17
JournalCancer immunology research
Volume6
Issue number12
DOIs
StatePublished - Dec 1 2018

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Pancreatic Neoplasms
Breast Neoplasms
Tumor Microenvironment
Neoplasms
Tumor-Infiltrating Lymphocytes
Gene Expression Profiling
Immunosuppressive Agents
T-Lymphocytes
Granzymes
Histone Deacetylase Inhibitors
Adaptive Immunity
Myeloid-Derived Suppressor Cells
entinostat
Epigenomics
Flow Cytometry
Therapeutics
Survival
Population

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. / Christmas, Brian J.; Rafie, Christine I.; Hopkins, Alexander C.; Scott, Blake A.; Ma, Hayley S.; Cruz, Kayla A.; Woolman, Skylar; Armstrong, Todd D; Connolly, Roisin; Azad, Nilofer; Jaffee, Elizabeth; Roussos Torres, Evanthia.

In: Cancer immunology research, Vol. 6, No. 12, 01.12.2018, p. 1561-1577.

Research output: Contribution to journalArticle

Christmas, Brian J. ; Rafie, Christine I. ; Hopkins, Alexander C. ; Scott, Blake A. ; Ma, Hayley S. ; Cruz, Kayla A. ; Woolman, Skylar ; Armstrong, Todd D ; Connolly, Roisin ; Azad, Nilofer ; Jaffee, Elizabeth ; Roussos Torres, Evanthia. / Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. In: Cancer immunology research. 2018 ; Vol. 6, No. 12. pp. 1561-1577.
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AU - Scott, Blake A.

AU - Ma, Hayley S.

AU - Cruz, Kayla A.

AU - Woolman, Skylar

AU - Armstrong, Todd D

AU - Connolly, Roisin

AU - Azad, Nilofer

AU - Jaffee, Elizabeth

AU - Roussos Torres, Evanthia

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