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Epitranscriptomics modifier pentostatin indirectly triggers Toll-like receptor 3 and can enhance immune infiltration in tumors


Tusup, Marina; Kündig, Thomas M; Pascolo, Steve (2022). Epitranscriptomics modifier pentostatin indirectly triggers Toll-like receptor 3 and can enhance immune infiltration in tumors. Molecular Therapy, 30(3):1163-1170.

Abstract

The adenosine deaminase inhibitor 2'-deoxycoformycin (pentostatin, Nipent) has been used since 1982 to treat leukemia and lymphoma, but its mode of action is still unknown. Pentostatin was reported to decrease methylation of cellular RNA. We discovered that RNA extracted from pentostatin-treated cells or mice has enhanced immunostimulating capacities. Accordingly, we demonstrated in mice that the anticancer activity of pentostatin required Toll-like receptor 3, the type I interferon receptor, and T cells. Upon systemic administration of pentostatin, type I interferon is produced locally in tumors, resulting in immune cell infiltration. We combined pentostatin with immune checkpoint inhibitors and observed synergistic anti-cancer activities. Our work identifies pentostatin as a new class of an anticancer immunostimulating drug that activates innate immunity within tumor tissues and synergizes with systemic T cell therapies.

Keywords: Nipent; TLR3; cold tumor; epitranscriptomics; hot tumor; immune checkpoint inhibitors; interferon; methylation index; pentostatin; tumor microenvironment.

Abstract

The adenosine deaminase inhibitor 2'-deoxycoformycin (pentostatin, Nipent) has been used since 1982 to treat leukemia and lymphoma, but its mode of action is still unknown. Pentostatin was reported to decrease methylation of cellular RNA. We discovered that RNA extracted from pentostatin-treated cells or mice has enhanced immunostimulating capacities. Accordingly, we demonstrated in mice that the anticancer activity of pentostatin required Toll-like receptor 3, the type I interferon receptor, and T cells. Upon systemic administration of pentostatin, type I interferon is produced locally in tumors, resulting in immune cell infiltration. We combined pentostatin with immune checkpoint inhibitors and observed synergistic anti-cancer activities. Our work identifies pentostatin as a new class of an anticancer immunostimulating drug that activates innate immunity within tumor tissues and synergizes with systemic T cell therapies.

Keywords: Nipent; TLR3; cold tumor; epitranscriptomics; hot tumor; immune checkpoint inhibitors; interferon; methylation index; pentostatin; tumor microenvironment.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Molecular Biology
Life Sciences > Genetics
Life Sciences > Pharmacology
Life Sciences > Drug Discovery
Uncontrolled Keywords:Drug Discovery, Pharmacology, Genetics, Molecular Biology, Molecular Medicine
Language:English
Date:1 March 2022
Deposited On:23 Nov 2021 16:41
Last Modified:25 Feb 2024 02:49
Publisher:Nature Publishing Group
ISSN:1525-0016
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ymthe.2021.09.022
PubMed ID:34563676
Project Information:
  • : FunderSNF
  • : Grant ID
  • : Project Title
  • Content: Accepted Version
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)