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Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

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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.

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Abbreviations

AML:

Acute myeloid leukemia

ASO:

Antisense oligonucleotide

CD:

Cluster of differentiation

CMM:

Cbfb/Myh11/Mpl

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

DC:

Dendritic cell

DLBCL:

Diffuse large B cell lymphoma

dODN:

Decoy oligodeoxynucleotide

Jak:

Janus kinase

MDSC:

Myeloid-derived suppressor cell

miRNA:

Micro RNA

MTD:

Maximum tolerated dose

NF-κB:

Nuclear factor κB

NHL:

Non-Hodgkin lymphoma

ODN:

Oligodeoxynucleotide

ONT:

Oligonucleotide therapeutic

PD-1:

Programmed cell death protein 1

PMN:

Polymorphonuclear

RAGE:

Receptor for advanced glycation endproducts

RT:

Radiation therapy

siRNA:

Short interfering RNA

STAT3:

Signal transducer and activator of transcription 3

TAM:

Tumor-associated macrophage

TF:

Transcription factor

TLR:

Toll-like receptor

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Acknowledgements

This work was supported in part by the National Cancer Institute/National Institutes of Health award number R01CA155367, P50CA107399, P30CA033572 (COH), the Department of Defense grant W81XWH-16-1-0499 and the STOP-CANCER Allison-Tovo-Dwyer Memorial Career-Development Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors are grateful to Dr. Peter Heinrich for critical reading of the manuscript and Dr. Sumanta Pal for thoughtful comments and suggestions.

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  1. Department of Immuno-Oncology at Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA

    Marcin Kortylewski & Dayson Moreira

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  1. Marcin Kortylewski
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  2. Dayson Moreira
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Correspondence to Marcin Kortylewski.

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Kortylewski, M., Moreira, D. Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol Immunother 66, 979–988 (2017). https://doi.org/10.1007/s00262-017-1966-2

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  • DOI: https://doi.org/10.1007/s00262-017-1966-2

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