Discrepant antitumor efficacies of three CpG oligodeoxynucleotide classes in monotherapy and co-therapy with PD-1 blockade

Li, Tete; Cong, Hua; Yue, Wenjun; Wu, Jing; Lv, Xinping; Wei, Qiuyu; Zhu, Shan; Zang, Guoxia; Cui, Jiuwei; Liu, Yongjun; Chen, Jingtao

doi:10.1016/j.phrs.2020.105293

Cited by 22 publications

(16 citation statements)

References 39 publications

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“…A similar apoptotic mechanism was observed in ODN 7909 treatments where the CpG ODN could promote radio-sensitization via p53-dependent apoptosis pathway and enhance Th1 cytokine production in combination with radiotherapy [61,62]. Different from class A CpG ODNs, multiple studies demonstrated that class B CpG ODNs could have the potential of regulating PD-1/PD-L1 expressions [63][64][65].…”

Section: Cpg Odn Classification and Antitumor Efficacymentioning

confidence: 68%

“…In a study comparing the immunostimulatory activity of all three types of classical CpG ODNs, class C CpG ODNs demonstrated higher efficiency in mediating NK cell-dependent cytotoxicity compared to class A and class B CpG ODNs, although class A CpG ODNs still produced the highest IFNγ in favoring of CTL activation [66]. In recent studies, class C CpG ODNs were superior in B cell stimulation, NF-κB activation, and memory T cell activation to class B CpG ODNs [63].…”

Section: Cpg Odn Classification and Antitumor Efficacymentioning

confidence: 99%

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CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

et al. 2021

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CpG oligodeoxynucleotides (CpG ODNs), the artificial versions of unmethylated CpG motifs that were originally discovered in bacterial DNA, are demonstrated not only as potent immunoadjuvants but also as anticancer agents by triggering toll-like receptor 9 (TLR9) activation in immune cells. TLR9 activation triggered by CpG ODN has been shown to activate plasmacytoid dendritic cells (pDCs) and cytotoxic T lymphocytes (CTLs), enhancing T cell-mediated antitumor immunity. However, the extent of antitumor immunity carried by TLR agonists has not been optimized individually or in combinations with cancer vaccines, resulting in a decreased preference for TLR agonists as adjuvants in clinical trials. Although various combination therapies involving CpG ODNs have been applied in clinical trials, none of the CpG ODN-based drugs have been approved by the FDA, owing to the short half-life of CpG ODNs in serum that leads to low activation of natural killer cells (NK cells) and CTLs, along with increases of pro-inflammatory cytokine productions. This review summarized the current innovation on CpG ODNs that are under clinical investigation and explored the future direction for CpG ODN-based nanomedicine as an anticancer monotherapy.

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Section: Cpg Odn Classification and Antitumor Efficacymentioning

confidence: 68%

Section: Cpg Odn Classification and Antitumor Efficacymentioning

confidence: 99%

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

et al. 2021

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“…Several TLR9 DNA agonists used as adjuvants for vaccines against cancer or infectious diseases are in clinical trials, although none are being tested on gastric cancer 36 . In summary, the current study suggests that TLR9 activation and subsequent IFNα production helps to shape the immune microenvironment preceding tumor development and that suppression of DAMP pathway components might ultimately be therapeutic targets to consider for cancer monotherapy or co-therapy 37 .…”

Section: Discussionmentioning

confidence: 84%

Toll Like Receptor 9 Pathway Mediates Schlafen⁺-MDSC Polarization During Helicobacter-Induced Gastric Metaplasias

Ding

Chakrabarti

Sheriff

et al. 2022

Preprint

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Background and Aims: A subset of MDSCs that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter-inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that individuals with a more robust response to damage-activated molecular patterns (DAMPs) and increased Toll-like receptor (TLR9) expression are predisposed to the neoplastic complications of Helicobacter infection. Methods: A mouse or human Transwell™ co-culture system comprised of dendritic cells (DCs), 2-dimensional gastric epithelial monolayers and Helicobacter were used to dissect the cellular source of interferon (IFNα) in the stomach by flow cytometry. Conditioned media from the co-cultures polarized primary myeloid cells. Myeloid-derived suppressor cell (MDSC) activity was determined by T cell suppression assays. In human subjects with intestinal metaplasia or gastric cancer, the rs5743836 TLR9T>C variant was genotyped and linked to TLR9, IFNα and SLFN12L expression by immunohistochemistry. NFκB binding to the TLR9 C allele was determined by electrophoretic mobility shift assays. Results: Helicobacter infection induced gastric epithelial and plasmacytoid DC expression of TLR9 and IFNα. Co-culturing primary mouse or human cells with DCs and Helicobacter induced TLR9, IFNα secretion and SLFN+-MDSC polarization. Neutralizing IFNα in vivo mitigated Helicobacter-induced SPEM. The TLR9 minor C allele creates an NFκB binding site associated with higher levels of TLR9, IFNαand SLFN12L in Helicobacter-infected stomachs that correlated with a greater incidence of metaplasias and cancer. Conclusion: TLR9 plays an essential role in the production of IFNα and polarization of SLFN+-MDSCs upon Helicobacter infection. Subjects carrying the rs5743836 TLR9 minor C allele are predisposed to neoplastic complications if chronically infected.

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“…37, [66][67][68][69][70][71][72] Since CpG ODN has the ability to initiate immune activation and destroy immunosuppression in the TME, it has been applied to treat various cancers in preclinical and clinical studies. 56 Nevertheless, compared with CpG ODN loaded in nanovaccines, the immune effect of free CpG ODN in clinical research did seem to be discouraging. It is well known that the cell membranes and CpG ODNs are generally negatively charged, which have a high probability of causing electrostatic repulsion to make it difficult for CpG ODN being taken up by the cells.…”

Section: Cpg-based Nanovaccines For Cancer Immunotherapymentioning

confidence: 99%

“…34,40 Since the discovery of the powerful immunostimulating activity of Type B CpG ODN, it has been widely used in preclinical and clinical research in the field of disease treatment. 56 For example, Type B CpG ODN has been developed as an immune adjuvant for hepatitis B virus (HBV) vaccine. Compared with the original HBV vaccine (hepatitis B surface antigen + alum), the HBV vaccine loaded with Type B CpG ODN has better immunostimulation ability to produce protective antibodies faster for achieving better preventive effect, and the vaccine is already in the advanced stage of clinical trials, which has good potential to replace the original HBV vaccine.…”

mentioning

confidence: 99%

CpG-Based Nanovaccines for Cancer Immunotherapy

Chen¹,

Jiang²,

Yu³

et al. 2021

IJN

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Cancer has been a serious health hazard to the people all over the world with its high incidence and horrible mortality. In recent years, tumor vaccines in immunotherapy have become a hotspot in cancer therapy due to their many practical advantages and good therapeutic potentials. Among the various vaccines, nanovaccine utilized nanoparticles (NPs) as the carrier and/or adjuvant has presented significant therapeutic effect in cancer treatment. For tumor nanovaccines, unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) is a commonly used adjuvant. It has been reported that CpG ODN was the most effective immune stimulant among the currently known adjuvants. It could be recognized by toll-like receptor 9 (TLR9) to activate humoral and cellular immunity for preventing or treating cancer. In this review, the topic of CpG-based nanovaccines for cancer immunotherapy will be focused. The types and properties of different CpG will be introduced in detail first, and then some representative tumor nanovaccines will be reviewed according to the diverse loading modes of CpG, such as electrostatic adsorption, covalent bonding, hydrophilic and hydrophobic interaction, and DNA self-assembly, for summarizing the current progress of CpG-based tumor nanovaccines. Finally, the challenges and future perspectives will be discussed. It is hoped that this review will provide valuable references for the development of nanovaccines in cancer immunotherapy.

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Discrepant antitumor efficacies of three CpG oligodeoxynucleotide classes in monotherapy and co-therapy with PD-1 blockade

Cited by 22 publications

References 39 publications

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

Toll Like Receptor 9 Pathway Mediates Schlafen⁺-MDSC Polarization During Helicobacter-Induced Gastric Metaplasias

CpG-Based Nanovaccines for Cancer Immunotherapy

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Discrepant antitumor efficacies of three CpG oligodeoxynucleotide classes in monotherapy and co-therapy with PD-1 blockade

Cited by 22 publications

References 39 publications

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

Toll Like Receptor 9 Pathway Mediates Schlafen+-MDSC Polarization During Helicobacter-Induced Gastric Metaplasias

CpG-Based Nanovaccines for Cancer Immunotherapy

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Toll Like Receptor 9 Pathway Mediates Schlafen⁺-MDSC Polarization During Helicobacter-Induced Gastric Metaplasias