title: Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells.
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.
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: KiBem
authors: K
authors: Kim
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: Andrew D
authors: AD
authors: Skora
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: Zhaobo
authors: Z
authors: Li
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: Qiang
authors: Q
authors: Liu
authors: Oncology Flow Cytometry Core Facility, and.
authors: Ada J
authors: AJ
authors: Tam
authors: Oncology Flow Cytometry Core Facility, and.
authors: Richard L
authors: RL
authors: Blosser
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: Luis A
authors: LA
authors: Diaz
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: Nickolas
authors: N
authors: Papadopoulos
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
authors: Kenneth W
authors: KW
authors: Kinzler
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center,Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287 bertvog@gmail.com sbzhou@jhmi.edu.
authors: Bert
authors: B
authors: Vogelstein
authors: Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, bertvog@gmail.com sbzhou@jhmi.edu.
authors: Shibin
authors: S
authors: Zhou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage; D001549:Benzamides / Q000008:administration & dosage; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D003131:Combined Modality Therapy; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D011725:Pyridines / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D001549:Benzamides; D060908:CTLA-4 Antigen; D056572:Histone Deacetylase Inhibitors; C491383:Pdcd1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061026:Programmed Cell Death 1 Receptor; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine
keywords: 5-azacytidine; HDAC; entinostat; exome; methyltransferase