title: Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities.
abstract: Immunotherapies emerged as an alternative for cancer treatment, yet their clinical efficacies are still limited, especially in case of solid tumors. Myeloid immune cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), are often hijacked by tumors and become pivotal inhibitors of antitumor immunity. Immunosuppressive functions of tumor-associated myeloid cells result from the activity of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor with well-defined tumorigenic and tolerogenic roles in human cancers. To overcome challenges in the development of pharmacological STAT3 inhibitors, we recently developed oligonucleotide-based strategies for cell-selective, in vivo STAT3 targeting. Conjugation of a STAT3siRNA or decoy STAT3 inhibitors to synthetic Toll-like Receptor 9 (TLR9) agonists, CpG oligonucleotides, allowed for selective delivery into TLR9-positive cells. Cellular target for CpG-STAT3 inhibitors include non-malignant, tumor-associated myeloid cells, such as polymorphonuclear MDSCs, as well as cancer cells in acute myeloid leukemia, B cell lymphoma and in certain solid tumors. The chemically modified CpG-STAT3 inhibitors resist serum nucleases and thus can be administered intravenously. Their potency relies on the intracellular gain-of-function effect: release of the central immune checkpoint regulator (STAT3) to unleash proinflammatory signaling (CpG/TLR9) in the same antigen-presenting cell. At the cellular level, CpG-STAT3 inhibitors exert two-pronged effect by rescuing T cells from the immune checkpoint control while decreasing survival of cancer cells. In this article, we review the preclinical data on CpG-STAT3 inhibitors and discuss perspectives of using TLR9-targeted delivery of oligonucleotide therapeutics for the generation of novel, more effective and safer cancer immunotherapies.
authors.affiliation: Department of Immuno-Oncology at Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. mkortylewski@coh.org.
authors.forename: Marcin
authors.identifier: http://orcid.org/0000-0002-6003-1816
authors.initials: M
authors.lastname: Kortylewski
authors.affiliation: Department of Immuno-Oncology at Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA.
authors.forename: Dayson
authors.initials: D
authors.lastname: Moreira
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D058990:Molecular Targeted Therapy; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009841:Oligonucleotides / Q000235:genetics / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; D051217:Toll-Like Receptor 9
keywords: CpG; MDSC; Oligonucleotides; Regulatory myeloid suppressor cells; STAT3; TLR9