Toll-Like Receptor-4 Modulation for Cancer Immunotherapy

Awasthi, Shanjana

doi:10.3389/fimmu.2014.00328

Cited by 60 publications

(55 citation statements)

References 72 publications

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“…The inhibition by M3G of LPS-induced activation of TLR4 is a novel finding, albeit expected since similar results have been obtained using other opioids, namely morphine, fentanyl, naltrexone, and β-funaltrexamine (β-FNA) (Stevens et al, 2013). Immunomodulating drugs targeting TLR4 are actively investigated in cancer, where TLR4 persistent activation can induce chronic inflammatory conditions contributing to carcinogenesis, while TLR4 agonists can induce anti-tumor immunity (Awasthi, 2014). A TLR4-active agent that promotes anti-tumor immunity while decreasing inflammatory response would be valuable in cancer therapy (Awasthi, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Immunomodulating drugs targeting TLR4 are actively investigated in cancer, where TLR4 persistent activation can induce chronic inflammatory conditions contributing to carcinogenesis, while TLR4 agonists can induce anti-tumor immunity (Awasthi, 2014). A TLR4-active agent that promotes anti-tumor immunity while decreasing inflammatory response would be valuable in cancer therapy (Awasthi, 2014). It would be interesting to assess opioids in this context, including M3G, whose activity at TLR4 is proposed to be mediated by its glucuronidated moiety on the carbon number 3 (Lewis et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

Khabbazi

Xie

et al. 2016

Front. Pharmacol.

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Macrophages are abundant in the tumor microenvironment where they adopt a pro-tumor phenotype following alternative polarization induced by paracrine factors from cancer and stromal cells. In contrast, classically activated macrophages have tumoricidal activities, such that the polarization of tumor-associated macrophages has become a novel therapeutic target. Toll-like receptor 4 engagement promotes classical activation of macrophages, and recent literature suggests TLR4 agonism to prevent metastasis and promote survival in experimental metastasis models. A growing number of studies indicate that TLR4 can respond to opioids, including the opioid receptor-inactive morphine metabolite morphine-3-glucuronide (M3G). We measured the activation of TLR4 in a reporter cell line exogenously expressing TLR4 and TLR4 co-receptors, and confirmed that M3G weakly but significantly activates TLR4. We hypothesized that M3G would promote the expression of classical activation signature genes in macrophages in vitro. We exposed mouse and human macrophage cell lines to M3G or the TLR4 activator lipopolysaccharide (LPS), alone or in combination with interferon gamma (IFN-γ). The classical macrophage activation markers tested were iNOS, CD86, IL-6, or TNF-α in RAW 264.7 cells and IL-6, IL-12, IL-23, TNF-α, CXCL10, and CXCL11 in THP1 cells. Our results show that despite exhibiting TLR4-activation ability, M3G does not elicit the expression of classical activation markers in LPS-responsive macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

Khabbazi

Xie

et al. 2016

Front. Pharmacol.

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“…Авторы обнаружили, что наличие SNP в гене TLR4 связано с более слабым ответом на индукционную терапию главным образом у больных, получавших иммуномодулирующие препа-раты, но не бортезомиб. Показано, что изменчивость в генах иммунной системы коррелирует с различным ответом на противомиеломные препараты и оказы-вает влияние на течение болезни [124].…”

Section: кумулятивная доля выжившихunclassified

“…Особенности влияния изученных SNP на результаты отдельных видов терапии, вероятно, свидетельствуют о раз-личиях в механизмах действия препаратов на клетки ММ и их микроокружение. Таким образом, SNP, ко-торые обусловливают передачу сигналов TLR4 через NF-κB, связаны с эффективностью лекарственных средств, действующих на разных этапах пути NF-κB [124]. Считается, что мутации в генах TLR выступают в качестве прогностического маркера прогрессиро-вания опухолей [125].…”

Section: кумулятивная доля выжившихunclassified

Prognostic Value of Genetic Markers for Efficacy Estimation of Induction Treatment Including Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients

Nazarova¹,

Минаева²,

Хоробрых³

et al. 2018

Клиническая онкогематология

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Aim. To determine the value of polymorphisms of the immune response genes for the treatment efficacy in MM patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHSCT). Methods. The overall of 20 ММ patients (8 men and 12 women) were included in the study. The median age was 51.5 years (range 32-67). Clinical laboratory tests had been performed before melphalan high-dose (200 mg/m<sup>2</sup>) conditioning therapy. In accordance with the achieved anticancer response to induction treatment the patients were divided into 3 groups: patients with partial remission (group 1; n = 7); patients with very good partial remission (group 2; n = 9); patients with complete remission (group 3; n = 4). Genotyping of 20 polymorphic loci of 14 immune response genes was performed using PCR. Results. The study showed that group 2 had no AA mutant homozygotes of IL10 in the G-1082A polymorphic locus compared to group 3 and no TT mutant homozygotes of TLR6 (Ser249Pro) compared to group 1. The patients with more pronounced mucositis (grade 2/3) compared to patients with minor mucositis (grade 0/1) had no CC mutant homozygotes of IL1ß in the G-1473C position and a smaller number of (CT+TT) heterozygous and homozygous haplotype carriers of IL10 with the T mutant allele in the C-819T mutation point. The multivariate analysis showed that the genetic marker statistically effecting the progression-free survival rates in MM patients after high-dose chemotherapy and autoHSCT was the polymorphous status of the IL10 (G-1082A), TNF (G-308A), TLR4 (Thr399Ile), and TLR9 in the T-1237C and A2848 polymorphic loci. Progression-free survival rates correlated with the mutation status of IL1ß (T-511C), IL2 (T-330G), IL6 (C-174G), CD14 (C-159T), TLR3 (Phe421Leu), and TLR4 (Asp299Gly). Conclusion. The obtained data show the correlation of 14 polymorphisms of 10 immune response genes with the immediate results of the induction treatment, and also with the severity of mucositis during the early post-transplant period, as well as overall and progression-free survival rates in MM patients. Due to a small sample volume further studies will be planned with the aim to verify the identified trends. The suggested hypothesis for immune response gene polymorphism effecting a disease prognosis can substantially contribute to developing of individualized approach to MM treatment.

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“…[88] In the intervening forty-one years, the suggested uses for both agonistic and detoxified lipid A as immune modulators have exploded. [89–91] Notably, the first new adjuvant approved by the FDA in decades is a lipid A derivative. Monophosphoryl lipid A (MPLA, commonly MPL) is chemically derived from a deep rough (Re)-LPS strain of Salmonella enterica (serovar Minnesota R595).…”

Section: Effective Strategies For Lipid A-based Treatment Approaches mentioning

confidence: 99%

Lipid A structural modifications in extreme conditions and identification of unique modifying enzymes to define the Toll-like receptor 4 structure-activity relationship

Scott

Oyler

Goodlett

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Strategies utilizing Toll-like receptor 4 (TLR4) agonists for treatment of cancer, infectious diseases, and other targets report promising results. Potent TLR4 antagonists are also gaining attention as therapeutic leads. Though some principles for TLR4 modulation by lipid A have been described, a thorough understanding of the structure-activity relationship (SAR) is lacking. Only through a complete definition of lipid A-TLR4 SAR is it possible to predict TLR4 signaling effects of discrete lipid A structures, rendering them more pharmacologically relevant. A limited ‘toolbox’ of lipid A-modifying enzymes has been defined and is largely composed of enzymes from mesophile human and zoonotic pathogens. Expansion of this ‘toolbox’ will result from extending the search into lipid A biosynthesis and modification by bacteria living at the extremes. Here, we review the fundamentals of lipid A structure, advances in lipid A uses in TLR4 modulation, and the search for novel lipid A-modifying systems in extremophile bacteria.

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Toll-Like Receptor-4 Modulation for Cancer Immunotherapy

Cited by 60 publications

References 72 publications

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

The TLR4-Active Morphine Metabolite Morphine-3-Glucuronide Does Not Elicit Macrophage Classical Activation In Vitro

Prognostic Value of Genetic Markers for Efficacy Estimation of Induction Treatment Including Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients

Lipid A structural modifications in extreme conditions and identification of unique modifying enzymes to define the Toll-like receptor 4 structure-activity relationship

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