Abstract
Impressive responses have been observed in patients treated with checkpoint inhibitory anti-programmed cell death-1 (PD-1) or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti-PD-1 and anti-CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.
Keywords:
5-azacytidine; HDAC; entinostat; exome; methyltransferase.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Azacitidine / administration & dosage
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Benzamides / administration & dosage
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CTLA-4 Antigen / antagonists & inhibitors
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CTLA-4 Antigen / immunology
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Cell Line, Tumor
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / secondary
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Colorectal Neoplasms / therapy
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Combined Modality Therapy
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Epigenesis, Genetic / drug effects
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Female
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Histone Deacetylase Inhibitors / administration & dosage
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Humans
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Immunotherapy / methods*
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / secondary
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Mammary Neoplasms, Experimental / therapy
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Mice
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Mice, Inbred BALB C
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Myeloid Cells / drug effects
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Myeloid Cells / immunology*
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Neoplasm Metastasis / genetics
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Neoplasm Metastasis / immunology*
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Neoplasm Metastasis / therapy*
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Phosphoinositide-3 Kinase Inhibitors
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / immunology
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Pyridines / administration & dosage
Substances
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Antibodies, Monoclonal
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Benzamides
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CTLA-4 Antigen
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Histone Deacetylase Inhibitors
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Pdcd1 protein, mouse
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Phosphoinositide-3 Kinase Inhibitors
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Programmed Cell Death 1 Receptor
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Pyridines
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entinostat
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Azacitidine