Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer

Eskuri, Maarit; Kemi, Niko; Helminen, Olli; Huhta, Heikki; Kauppila, Joonas H

doi:10.1007/s00428-023-03635-1

Cited by 2 publications

(1 citation statement)

References 42 publications

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“…This could be circumvented if we would use a TCRlike antibody recognizing a neopeptide/MHC I complex on the tumor cells. The new strategy can be used for other types of cancer, e.g., oral squamous cell carcinoma expressing TLR9 [77] and gastric cancer expressing TLR4 [78,79].…”

Section: Discussionmentioning

confidence: 99%

TLR2 and TLR9 Blockade Using Specific Intrabodies Inhibits Inflammation-Mediated Pancreatic Cancer Cell Growth

Ajay,

Gasser,

Hsiao

et al. 2024

Antibodies

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Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) remains a deadly cancer worldwide with a need for new therapeutic approaches. A dysregulation in the equilibrium between pro- and anti-inflammatory responses with a predominant immunosuppressive inflammatory reaction in advanced stage tumors seem to contribute to tumor growth and metastasis. The current therapies do not include strategies against pro-tumorigenic inflammation in cancer patients. We have shown that the upregulated cell surface expression of Toll-like Receptor (TLR) 2 and of TLR9 inside PDAC cells maintain chronic inflammatory responses, support chemotherapeutic resistance, and mediate tumor progression in human pancreatic cancer. We further demonstrated intracellular TLR2 and TLR9 targeting using specific intrabodies, which resulted in downregulated inflammatory signaling. In this study, we tested, for the first time, an intrabody-mediated TLR blockade in human TLR2- and TLR9-expressing pancreatic cancer cells for its effects on inflammatory signaling-mediated tumor growth. Newly designed anti-TLR2- and anti-TLR9-specific intrabodies inhibited PDAC growth. Co-expression analysis of the intrabodies and corresponding human TLRs showed efficient retention and accumulation of both intrabodies within the endoplasmic reticulum (ER), while co-immunoprecipitation studies indicated both intrabodies interacting with their cognate TLR antigen within the pancreatic cancer cells. Cancer cells with attenuated proliferation expressing accumulated TLR2 and TRL9 intrabodies demonstrated reduced STAT3 phosphorylation signaling, while apoptotic markers Caspases 3 and 8 were upregulated. To conclude, our results demonstrate the TLR2 and TLR9-specific intrabody-mediated signaling pathway inhibition of autoregulatory inflammation inside cancer cells and their proliferation, resulting in the suppression of pancreatic tumor cell growth. These findings underscore the potential of specific intrabody-mediated TLR inhibition in the ER relevant for tumor growth inhibition and open up a new therapeutic intervention strategy for the treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

TLR2 and TLR9 Blockade Using Specific Intrabodies Inhibits Inflammation-Mediated Pancreatic Cancer Cell Growth

Ajay,

Gasser,

Hsiao

et al. 2024

Antibodies

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New Horizons in the Diagnosis of Gastric Cancer: The Importance of Selected Toll-like Receptors in Immunopathogenesis Depending on the Stage, Clinical Subtype, and Gender of Newly Diagnosed Patients

Kos,

Bojarski,

Mertowska

et al. 2024

IJMS

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Introduction: Toll-like receptors (TLRs) play a vital role in the innate immune response, recognizing pathogens and initiating the inflammatory response. Research suggests that TLRs may also have a significant impact on the development and progression of cancers, including gastric cancer (GC). Understanding the role of individual TLRs in the immunopathogenesis of gastric cancer may provide new information necessary to develop more effective diagnostic and therapeutic methods. Aim of the study: This study aimed to determine the role of selected TLR-2, -3, -4, and -9 in the immunopathogenesis of patients with newly diagnosed and untreated gastric cancer. Materials and methods: The study included 60 newly diagnosed, untreated GC patients and 25 healthy volunteers. The research included analyses assessing the percentage of the tested TLRs on T and B lymphocyte subpopulations using multicolor flow cytometry and assessing their concentration in the serum of the examined patients using ELISA tests. The statistical analyses performed included a comparison of patients in individual stages of gastric cancer, an analysis of the most common clinical subtypes of gastric cancer, and a comparative analysis of differences in the gender of recruited patients. Results: Our studies showed different expression levels of TLR-2, -3, -4, and -9 on T and B lymphocyte subpopulations, as well as their different concentrations in patients’ serum. Significant differences in the expression of these receptors were observed depending on the stage of gastric cancer and its clinical subtypes. These differences were also visible in the context of patient gender. Summary: The results of our studies suggest that TLR-2, -3, -4, and -9 may play an important role in the immunopathogenesis of gastric cancer. The differential expression of these receptors depending on the stage of the disease, clinical subtype, and gender of patients may have potential diagnostic and therapeutic significance. Further research is necessary to understand better the mechanisms of action of TLRs in gastric cancer and to apply this knowledge in clinical practice.

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Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer

Cited by 2 publications

References 42 publications

TLR2 and TLR9 Blockade Using Specific Intrabodies Inhibits Inflammation-Mediated Pancreatic Cancer Cell Growth

TLR2 and TLR9 Blockade Using Specific Intrabodies Inhibits Inflammation-Mediated Pancreatic Cancer Cell Growth

New Horizons in the Diagnosis of Gastric Cancer: The Importance of Selected Toll-like Receptors in Immunopathogenesis Depending on the Stage, Clinical Subtype, and Gender of Newly Diagnosed Patients

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