Targeting toll-like receptors on T cells as a therapeutic strategy against tumors

Ding, Renyi; Jiao, Anjun; Zhang, Baojun

doi:10.1016/j.intimp.2022.108708

Cited by 5 publications

(8 citation statements)

References 67 publications

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“…TLR agonists are used to activate T cell-mediated antitumor responses. The activation of both innate and adaptive immune responses using TLR agonists can improve tumor therapy [ 97 , 106 ].…”

Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

“…TLR7/8 agonists in clinical trials for therapeutic treatment have been reported in different clinical applications [97]. Although many of the TLR7/8 agonists applied in immune-mediated diseases were focused on viral infection, such as hepatitis B virus (HBV) or HIV, vaccines and adjuvant, such as IMQ for influenza vaccine [123] and HBV vaccine [124], more and more TLR7/8 agonists have been tried in cancer immunotherapy [8,97,106] and gene-modified adoptive cell therapies, including TLR signaling domains in CAR T-cells [6]. There is accumulating evidence suggesting that TLR signals play an important role in the regulation of hematopoietic stem/progenitor cells (HSPCs).…”

Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

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Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Sun

Zhang

et al. 2022

Biomark Res

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Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B.

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Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Sun

Zhang

et al. 2022

Biomark Res

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“…TLRs, recognizing pathogen-associated molecular patterns (PAMPs) in a variety of viruses and microorganisms, are the bridge between innate and adaptive immunity [ 1 , 2 ]. Among all of the TLRs, only TLR7/8 have small-molecule ligands, which are easier to obtain and modify than other biomacromolecules such as TLR4 and TLR9 ligands [ 3 ]. Recently, small-molecule TLR7 agonists have been widely investigated in the field of tumor immunotherapy through inducing tumor-specific immune responses and reducing the tumor growth [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Vaccine Containing a Novel Toll-like Receptor 7 Agonist and an Aluminum Adjuvant Exerts Antitumor Effects

Zhang

Liu

Zhou

et al. 2022

IJMS

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Mucin 1 (MUC1) has received increasing attention due to its high expression in breast cancer, in which MUC1 acts as a cancer antigen. Our group has been committed to the development of small-molecule TLR7 (Toll-like receptor 7) agonists, which have been widely investigated in the field of tumor immunotherapy. In the present study, we constructed a novel tumor vaccine (SZU251 + MUC1 + Al) containing MUC1 and two types of adjuvants: a TLR7 agonist (SZU251) and an aluminum adjuvant (Al). Immunostimulatory responses were first verified in vitro, where the vaccine promoted the release of cytokines and the expression of costimulatory molecules in mouse BMDCs (bone marrow dendritic cells) and spleen lymphocytes. Then, we demonstrated that SZU251 + MUC1 + Al was effective and safe against a tumor expressing the MUC1 antigen in both prophylactic and therapeutic schedules in vivo. The immune responses in vivo were attributed to the increase in specific humoral and cellular immunity, including antibody titers, CD4+, CD8+ and activated CD8+ T cells. Therefore, our vaccine candidate may have beneficial effects in the prevention and treatment of breast cancer patients.

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“…Under certain conditions, inflammation can counter tumor progression, and activation of effective antitumor immunity is considered a potent adjuvant therapy option ( 10 ). As recently reviewed, TLR stimulation in combination with chemotherapy or radiotherapy has been shown to be effective against tumor progression in multiple clinical trials ( 11 ). Immunotherapy with TLR agonists significantly improves the outcomes of radiation therapy (RT) in preclinical models ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…As recently reviewed, TLR stimulation in combination with chemotherapy or radiotherapy has been shown to be effective against tumor progression in multiple clinical trials ( 11 ). Immunotherapy with TLR agonists significantly improves the outcomes of radiation therapy (RT) in preclinical models ( 11 , 12 ). The antitumor immune response, which is triggered by tumor antigens released from irradiated tumor cells, is considered to be the main mechanism underlying this therapeutic effect ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

Schagdarsurengin

Breiding²,

Loose³

et al. 2022

Front. Oncol.

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The use of immune adjuvants such as toll-like receptor (TLR) agonists reflects a novel strategy in prostate cancer (PCa) therapy. However, interleukin-1 receptor associated kinase 1 (IRAK1), a central effector of TLR signaling, has been shown to be responsible for resistance to radiation-induced tumor cell death. In order to better understand the function and epigenetic regulation of IRAK1 in PCa, we performed in vitro cell culture experiments together with integrative bioinformatic studies using the latest single-cell RNA-sequencing data of human PCa and normal prostate (NOR), and data from The Cancer Genome Atlas. We focused on key effectors of TLR signaling, the Myddosome-complex components IRAK1, IRAK4 and MYD88 (myeloid differentiation primary response 88), and TRAF6 (tumor-necrosis-factor receptor associated factor 6). In PCa, IRAK1-mRNA was specifically enriched in luminal epithelial cells, representing 57% of all cells, whereas IRAK4 and MYD88 were predominantly expressed in leukocytes, and TRAF6, in endothelial cells. Compared to NOR, only IRAK1 was significantly overexpressed in PCa (Benjamini-Hochberg adjusted p<2x10-8), whereas the expression of IRAK4, MYD88, and TRAF6 was unchanged in PCa, and IRAK1-expression was inversely correlated with a specific differentially methylated region (IRAK1-DMR) within a predicted promoter region enriched for H3K27ac (Spearman correlation r<-0.36; Fisher’s test, p<10-10). Transcription factors with high binding affinities in IRAK1-DMR were significantly enriched for canonical pathways associated with viral infection and carcinogenic transformation in the Kyoto Encyclopedia of Gene and Genomes analysis. DU145 cells, exhibiting hypermethylated IRAK1-DMR and low IRAK1-expression, reacted with 4-fold increased IRAK1-expression upon combined treatment with 5-aza-2-deoxycytidine and trichostatin A, and were unresponsive to infection with the uropathogenic Escherichia coli strain UTI89. In contrast, PC3 and LNCaP cells, exhibiting hypomethylated IRAK1-DMR and high endogenous IRAK1-mRNA levels, responded with strong activation of IRAK1-expression to UTI89 infection. In summary, exclusive overexpression of IRAK1 was observed in luminal epithelial cells in PCa, suggesting it has a role in addition to Myddosome-dependent TLR signaling. Our data show that the endogenous epigenetic status of PCa cells within IRAK1-DMR is decisive for IRAK1 expression and should be considered as a predictive marker when selective IRAK1-targeting therapies are considered.

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Targeting toll-like receptors on T cells as a therapeutic strategy against tumors

Cited by 5 publications

References 67 publications

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Breast Cancer Vaccine Containing a Novel Toll-like Receptor 7 Agonist and an Aluminum Adjuvant Exerts Antitumor Effects

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

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