Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist
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 opsonizat...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2021-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/6/e002484.full |
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| author | George J Weiner Aliasger K Salem Shakoora A Sabree Andrew P Voigt Sue E Blackwell Ajaykumar Vishwakarma Michael S Chimenti |
| author_facet | George J Weiner Aliasger K Salem Shakoora A Sabree Andrew P Voigt Sue E Blackwell Ajaykumar Vishwakarma Michael S Chimenti |
| author_sort | George J Weiner |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4b2849718b58408bbeccee7f317793da |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4b2849718b58408bbeccee7f317793da2024-11-08T19:20:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-06-019610.1136/jitc-2021-002484Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonistGeorge J Weiner0Aliasger K Salem1Shakoora A Sabree2Andrew P Voigt3Sue E Blackwell4Ajaykumar Vishwakarma5Michael S Chimenti6Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA3 Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, USAMedical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAMedical Scientist Training Program, The University of Iowa Carver College of Medicine, Iowa City, IA, USAHolden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USALaboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USAIowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA, USABackground 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.https://jitc.bmj.com/content/9/6/e002484.full |
| spellingShingle | George J Weiner Aliasger K Salem Shakoora A Sabree Andrew P Voigt Sue E Blackwell Ajaykumar Vishwakarma Michael S Chimenti Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist Journal for ImmunoTherapy of Cancer |
| title | Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist |
| title_full | Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist |
| title_fullStr | Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist |
| title_full_unstemmed | Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist |
| title_short | Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist |
| title_sort | direct and indirect immune effects of cmp 001 a virus like particle containing a tlr9 agonist |
| url | https://jitc.bmj.com/content/9/6/e002484.full |
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