Direct And Indirect Immune Effects Of Cmp-001, A Virus Like Particle Containing A Tlr9 Agonist.
JOURNAL FOR IMMUNOTHERAPY OF CANCER(2021)
摘要
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-Q beta antibody response which results in opsonization of CMP-001 and uptake by plasmacytoid dendritic cells (pDCs) that then produce interferon (IFN)-alpha. IFN-alpha 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-Q beta-coated CMP-001 were evaluated by flow cytometry and single-cell RNA sequencing. Purified monocytes were treated with anti-Q beta-coated CMP-001 or recombinant IFN-alpha to evaluate direct and secondary effects of anti-Q beta-coated CMP-001 on monocytes. Results Monocytes had the highest per cell uptake of anti-Q beta-coated CMP-001 with lower levels of uptake by pDCs and other cell types. Treatment of PBMCs with anti-Q beta-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-Q beta-coated CMP-001 on monocytes was indirect and mediated by IFN-alpha, but uptake of anti-Q beta-coated CMP-001 altered the monocytic response to IFN-alpha 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-Q beta-coated CMP-001 induces IFN-alpha production by pDCs which has secondary effects on a variety of cells including monocytes. Uptake of anti-Q beta-coated CMP-001 by monocytes alters their response to IFN-alpha, 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-Q beta-coated CMP-001 and provide insight into pathways that may be targeted to further enhance the efficacy of this novel approach to immunotherapy.
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关键词
immunotherapy, tumor microenvironment
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