The Toll–Like Receptor 2/6 Agonist, FSL–1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

Kurkjian, Cathryn J.; Guo, Hao; Montgomery, Nathan D.; Cheng, Ning; Yuan, Hong; Merrill, Joseph R.; Sempowski, Gregory D.; Brickey, W. June

doi:10.1038/s41598-017-17729-9

Cited by 24 publications

(15 citation statements)

References 48 publications

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“…In addition, damage of radiation exposure from cancer radiotherapy is unavoidable ( Singh et al, 2015 ). Of note, activation of TLRs can also contribute to hematopoietic replenishment as its up-regulation of growth factor G-CSF, alleviating the intrinsic repair to radiant injuries ( Singh et al, 2012 ; Kurkjian et al, 2017 ).…”

Section: Tlrs and Immune Systemmentioning

confidence: 99%

The Role of Toll-Like Receptor in Inflammation and Tumor Immunity

2018

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Toll-like receptors (TLRs) activation enables host to recognize a large number of pathogen-associated molecule patterns (PAMPs), ignite immune cells to discriminate between self and non-self, and then promote the following innate and adaptive immune responses. Accumulated clinical/preclinical evidences have proven TLRs to be critical role in the autoimmune diseases, including inflammatory and tumor-associated diseases. Activation of TLRs is becoming or has been a target for cancer treatment. It is shown that TLRs can induce preferable anti-tumor effect by eliciting inflammatory cytokines expression and cytotoxic T lymphocytes (CTLs) response. As adjuvant, TLRs agonists can launch a strong immune response to assist cancer radiotherapy and bio-chemotherapy. On the other hand, tumor-associated antigens acting as PAMPs, can also activate TLRs and induce tumor gene-related programmed cell death, including apoptosis, autophagy and programmed necrosis. While there are also arguments that the excessive TLRs expression will promote tumor deterioration in various organisms, as the TLR-induced inflammation will accelerate the cancer cells boost in the tumor microenvironment (TME). However, the effect of TLRs acting on cancers is still not quite clear today. In this review, we will summarize the recent researches of TLRs in cancer treatment and their role in TME, giving a brief overview on future expectation.

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Section: Tlrs and Immune Systemmentioning

confidence: 99%

The Role of Toll-Like Receptor in Inflammation and Tumor Immunity

2018

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“…Kurkjian et al reported that the synthetic TLR2/6 agonist, fibroblast-stimulating lipopeptide (FSL-1), prolonged survival in male and female mice after 24 h of radiation 64 . FSL-1 has been shown to not only promote hematopoiesis in bone marrow, spleen, and periphery but also to increase systemic levels of hematopoiesis-stimulating factors 65 .…”

Section: Combined Application Of Tlrs With Other Cancer Treatmentsmentioning

confidence: 99%

The Role of Toll-Like Receptors in Oncotherapy

2019

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Toll-like receptors (TLRs) are associated with tumor growth and immunosuppression, as well as apoptosis and immune system activation. TLRs can activate apoptosis and innate and adaptive immunity pathways, which can be pharmacologically targeted for the development of anticancer oncotherapies. Several studies and clinical trials indicate that TLR agonists are promising adjuvants or elements of novel therapies, particularly when used in conjunction with chemotherapy or radiotherapy. An increasing number of studies suggest that the activation of TLRs in various cancer types is related to oncotherapy; however, before this finding can be applied to clinical practice, additional studies are required. Research suggests that TLR agonists may have potential applications in cancer therapy; nevertheless, because TLR signaling can also promote tumorigenesis, a critical and comprehensive evaluation of TLR action is warranted. This review focuses on recent studies that have assessed the strengths and weaknesses of utilizing TLR agonists as potential anticancer agents.

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“…PSK has significantly inhibited the breast cancer growth via stimulation of CD8 T cells and natural killer (NK) cells. Other TLR2 agonists or their modified forms, lipopeptides also have been reported to be useful for the cancer treatment, which further suggests the potential of TLR2 agonist as effective enhancers for cancer immunotherapies . However, the current known TLR2 agonists, lipopeptides or their derivatives, are having limitations because of the difficulties in synthesis, susceptibility to hydrolysis, as well as in eliciting inflammatory cytokine storm.…”

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confidence: 99%

TLR1/2 Specific Small‐Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes

et al. 2019

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Toll‐like receptor 2 (TLR2) expressed on antigen presenting cells evokes a series of critical cytokines, which favor the development of tumor‐specific cytotoxic T lymphocytes (CTLs). Therefore, TLR2 represents an attractive cancer immunotherapeutic target. Here, a synthetic library of 14 000 compounds together with a series of newly developed compounds for NF‐κB activation using HEK‐Blue hTLR2 cells is initially screened. Following further screening in a variety of cells including HEK‐Blue hTLRs reporter cells, murine, and human macrophage cell lines, a potent small molecule agonist 23 (SMU‐Z1) is identified, which specifically activates TLR2 through its association with TLR1, with a EC 50 of 4.88 ± 0.79 × 10 −9 m . Toxicology studies, proinflammatory cytokines (e.g., TNF‐α, IL‐1β, IL‐6, and nitric oxide) and target‐protein based biophysical assays demonstrate the pharmacologically relevant characteristics of SMU‐Z1. In addition, SMU‐Z1 promotes murine splenocyte proliferation and upregulates the expression of CD8 + T cells, NK cells and DCs, which results in a significant antitumor effect in a murine leukemia model. Finally, the induced tumors in three out of seven mice disappear after administration of SMU‐Z1. Our studies thus identify a novel and potent TLR1/2 small molecule agonist, which displays promising immune adjuvant properties and antitumor immunity.

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The Toll–Like Receptor 2/6 Agonist, FSL–1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

Cited by 24 publications

References 48 publications

The Role of Toll-Like Receptor in Inflammation and Tumor Immunity

The Role of Toll-Like Receptor in Inflammation and Tumor Immunity

The Role of Toll-Like Receptors in Oncotherapy

TLR1/2 Specific Small‐Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes

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