Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist.

Autor:	Sabree SA; Interdisciplinary Graduate Program in Immunology, The University of Iowa, Iowa City, IA, USA.; Medical Scientist Training Program, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA., Voigt AP; Medical Scientist Training Program, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.; Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA., Blackwell SE; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA., Vishwakarma A; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Division of Pharmaceutics and Translational Therapeutics, The University of Iowa College of Pharmacy, Iowa City, IA, USA., Chimenti MS; Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA, USA., Salem AK; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA.; Division of Pharmaceutics and Translational Therapeutics, The University of Iowa College of Pharmacy, Iowa City, IA, USA., Weiner GJ; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA george-weiner@uiowa.edu.; Division of Pharmaceutics and Translational Therapeutics, The University of Iowa College of Pharmacy, Iowa City, IA, USA.; Department of Internal Medicine, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Jun; Vol. 9 (6).
DOI:	10.1136/jitc-2021-002484
Abstrakt:	Background: CMP-001, also known as vidutolimod, is a virus-like particle containing a TLR9 agonist that is showing promise in early clinical trials. Our group previously demonstrated that the immunostimulatory effects of CMP-001 are dependent on an anti-Qβ antibody response which results in opsonization of CMP-001 and uptake by plasmacytoid dendritic cells (pDCs) that then produce interferon (IFN)-α. IFN-α then leads to an antitumor T-cell response that is responsible for the in vivo efficacy of CMP-001. Here, we explore mechanisms by which the initial effects of CMP-001 on pDCs activate other cells that can contribute to development of an antitumor T-cell response. Methods: Uptake of CMP-001 by various peripheral blood mononuclear cell (PBMC) populations and response to anti-Qβ-coated CMP-001 were evaluated by flow cytometry and single-cell RNA sequencing. Purified monocytes were treated with anti-Qβ-coated CMP-001 or recombinant IFN-α to evaluate direct and secondary effects of anti-Qβ-coated CMP-001 on monocytes. Results: Monocytes had the highest per cell uptake of anti-Qβ-coated CMP-001 with lower levels of uptake by pDCs and other cell types. Treatment of PBMCs with anti-Qβ-coated CMP-001 induced upregulation of IFN-responsive genes including CXCL10, PDL1, and indoleamine-2,3-dioxygenase (IDO) expression by monocytes. Most of the impact of anti-Qβ-coated CMP-001 on monocytes was indirect and mediated by IFN-α, but uptake of anti-Qβ-coated CMP-001 altered the monocytic response to IFN-α and resulted in enhanced expression of PDL1, IDO, and CD80 and suppressed expression of CXCL10. These changes included an enhanced ability to induce autologous CD4 T-cell proliferation. Conclusions: Anti-Qβ-coated CMP-001 induces IFN-α production by pDCs which has secondary effects on a variety of cells including monocytes. Uptake of anti-Qβ-coated CMP-001 by monocytes alters their response to IFN-α, resulting in enhanced expression of PDL1, IDO and CD80 and suppressed expression of CXCL10. Despite aspects of an immunosuppressive phenotype, these monocytes demonstrated increased ability to augment autologous CD4 T-cell proliferation. These findings shed light on the complexity of the mechanism of action of anti-Qβ-coated CMP-001 and provide insight into pathways that may be targeted to further enhance the efficacy of this novel approach to immunotherapy. Competing Interests: Competing interests: SEB holds stock options in Checkmate Pharmaceuticals. GJW received research funding from Checkmate Pharmaceuticals. All of the other authors declare no competing interests. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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