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

BackgroundCMP-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.MethodsUptake 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.ResultsMonocytes 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.ConclusionsAnti-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.

Download Full-text

Cutting Edge: Contribution of Lung-Resident T Cell Proliferation to the Overall Magnitude of the Antigen-Specific CD8 T Cell Response in the Lungs following Murine Influenza Virus Infection

The Journal of Immunology ◽

10.4049/jimmunol.0901109 ◽

2009 ◽

Vol 183 (7) ◽

pp. 4177-4181 ◽

Cited By ~ 60

Author(s):

Jodi McGill ◽

Kevin L. Legge

Keyword(s):

Cell Proliferation ◽

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Cell Response ◽

Influenza Virus Infection ◽

Cd8 T Cell ◽

T Cell Response ◽

Cutting Edge ◽

T Cell Proliferation

Download Full-text

CTLA-4 expressed by human dendritic cells modulates thei cytokine secretion and induction of T cell proliferation

Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale ◽

10.4081/jbr.2011.4651 ◽

2011 ◽

Vol 84 (1) ◽

Author(s):

S. Laurent ◽

P. Carrega ◽

D. Saverino ◽

P. Piccioli ◽

M. Camoriamo ◽

...

Keyword(s):

Cell Proliferation ◽

Dendritic Cells ◽

T Cell ◽

Cytokine Production ◽

T Cell Response ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Human Monocytes ◽

Enhanced Secretion ◽

Human Dendritic Cells

<p>CTLA-4 is the major nefative regulator of T cell response. We have analyzed the expression of CTLA-4 in human monocytes and monocyte-derived DCs and the effects of its engagement on cytokine production and T cell stimulatory activity by mature DCs (mDCs). We found the CTLA-4 was highly expressed on freshly isolated monocytes, then down-modulated on the immature DCs (iDCs) and upregulated on mDCs. Treatment of mDCS with an agonistic anti-CTLA-4 m Ab enhanced secretion of IL-10 but reduced secretion of IL-8 and IL-12, as well as autologous CD4* T-cell proliferation in response to simulation with PPD recall antigenloaded-DCs. Neutralization of IL-10 with an anti-IL-10 antibody partially restored the ability of anti-CTLA-4-treated mDCs to stimulate T cell proliferation in response to PPD. Our data provide the first evidence that CTLA-4 receptor is expressed by human mDCs and exerts immune modulatory effects in these cells.</p>

Download Full-text

Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02604-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hongda Wang ◽

Yiming Zhao ◽

Bingbing Ren ◽

Yafei Qin ◽

Guangming Li ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Liver Function ◽

Cell Response ◽

T Cell Response ◽

T Cell Proliferation ◽

Endometrial Regenerative Cells ◽

Regenerative Cells

Abstract Background Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. Methods ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. Results After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. Conclusions The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.

Download Full-text