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Hsu CY, Jasim SA, Rasool KH, H M, Kaur J, Jabir MS, Alhajlah S, Kumar A, Jawad SF, Husseen B. Divergent functions of TLRs in gastrointestinal (GI) cancer: Overview of their diagnostic, prognostic and therapeutic value. Semin Oncol 2025; 52:152344. [PMID: 40347779 DOI: 10.1016/j.seminoncol.2025.152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 05/14/2025]
Abstract
The relationship between the innate immune signal and the start of the adaptive immune response is the central idea of this theory. By controlling the inflammatory and tissue-repair reactions to damage, the Toll-like receptors (TLRs), as a family of PRRs, have attracted increasing attention for its function in protecting the host against infection and preserving tissue homeostasis. Microbial infection, damage, inflammation, and tissue healing have all been linked to the development of malignancies, especially gastrointestinal (GI) cancers. Recently, increased studies on TLR recognition and binding, as well as their ligands, have significantly advanced our knowledge of the various TLR signaling pathways and offered therapy options for GI malignancies. Upon activation by pathogen-associated or damage-associated molecular patterns (DAMPs and PAMPs), TLRs trigger key pathways like NF-κB, MAPK, and IRF. NF-κB activation promotes inflammation, cell survival, and proliferation, often contributing to tumor growth, metastasis, and therapy resistance. MAPK pathways similarly drive uncontrolled cell growth and invasion, while IRF pathways modulate interferon production, yielding both anti-tumor and protumor effects. The resulting chronic inflammatory environment within tumors can foster progression, yet TLR activation can also stimulate beneficial anti-tumor immune responses. However, the functions of TLR expression in GI cancers and their diagnostic and prognostic along with therapeutic value have not yet entirely been elucidated. Understanding how TLR activation contributes to anti-cancer immunity against GI malignancies may hasten immunotherapy developments and increase patient survival.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona, USA
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Anbar, Iraq; Biotechnology Department, College of Applied Science, Fallujah University, Fallujah, Iraq
| | - Khetam Habeeb Rasool
- Department of Biology, College of Science, University of Mustansiriyah, Mustansiriyah, Iraq
| | - Malathi H
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Jaswinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Mohali, Punjab, India
| | - Majid S Jabir
- Department of Applied Sciences, University of Technology, Anbar, Iraq
| | - Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia.
| | - Abhinav Kumar
- Department of Nuclear and Renewable Energy, Ural Federal University Named after the First President of Russia Boris Yeltsin, Ekaterinburg, Russia; Centre for Research Impact & Outcome, Chitkara University, Rajpura, Punjab, India; Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, India
| | - Sabrean F Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hillah, Babylon, Iraq
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq; Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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Wang K, Huang H, Zhan Q, Ding H, Li Y. Toll-like receptors in health and disease. MedComm (Beijing) 2024; 5:e549. [PMID: 38685971 PMCID: PMC11057423 DOI: 10.1002/mco2.549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 03/17/2024] [Accepted: 03/26/2024] [Indexed: 05/02/2024] Open
Abstract
Toll-like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation-related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR-related diseases.
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Affiliation(s)
- Kunyu Wang
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Hanyao Huang
- Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
| | - Qi Zhan
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Haoran Ding
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Yi Li
- Department of Head and Neck Oncology Surgery, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengduChina
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Li H, Sun X, Zhao Y, Zhang C, Jiang K, Ren J, Xing L, He M. Pan-cancer analysis of TASL: a novel immune infiltration-related biomarker for tumor prognosis and immunotherapy response prediction. BMC Cancer 2023; 23:528. [PMID: 37296415 DOI: 10.1186/s12885-023-11015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND New immunotherapeutic strategies based on predictors are urgently needed. Toll-like receptor adaptor interacting with SLC15A4 on the lysosome (TASL) was recently confirmed to fulfill an important role in the innate immune response. However, whether TASL is involved in tumor development and immunotherapy response prediction has not been reported. METHODS TCGA and GTEx were used to yield transcriptional, genetic, and epigenetic levels of TASL in 33 cancer types. CIBERSORT was used to explore the correlation between TASL expression and multiple immune-related signatures and tumor-infiltrating immune cell content in different cancer types. The ability of TASL to predict tumor immunotherapy response was analyzed in seven datasets. Finally, we tested TASL expression in human glioma cell lines and tissue samples and analyzed its correlation with clinicopathological parameters. RESULTS TASL is widely heterogeneous at the transcriptional, genetic, and epigenetic levels. High TASL expression is an independent poor prognostic factor for immune "cold" tumor Low-Grade Glioma (LGG) but an opposite factor for "hot" tumors Lung Adenocarcinoma (LUAD) and Skin Cutaneous Melanoma (SKCM). TASL may affect tumor immune infiltration by mediating tumor-infiltrating lymphocytes and tumor-associated macrophages. It may differentially affect the prognosis of the three cancers by regulating the immunosuppressive microenvironment in LGG and the immunostimulatory microenvironment in LUAD and SKCM. High TASL expression is a potential biomarker for the positive response to immunotherapy in cancers such as SKCM and was also experimentally confirmed to be positively associated with adverse clinicopathological features of gliomas. CONCLUSION TASL expression is an independent prognostic factor for LGG, LUAD, and SKCM. High TASL expression is a potential biomarker for the positive response to immunotherapy in certain cancer types such as SKCM. Further basic studies focusing on TASL expression and tumor immunotherapy are urgently needed.
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Affiliation(s)
- Huanyu Li
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China
| | - Xiaoyu Sun
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China
| | - Yanyun Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China
| | - Changzhu Zhang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China
| | - Kai Jiang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China
| | - Jie Ren
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China.
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China.
| | - Lijuan Xing
- Precision Laboratory, Panjin Central Hospital, Panjin, 124000, Liaoning Province, China.
| | - Miao He
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning Province, China.
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Key Laboratory of Precision Diagnosis and Treatment of GastrointestinalTumors (China Medical University), Ministry of Education, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, 110122, Liaoning Province, China.
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Villarroel-Espindola F, Ejsmentewicz T, Gonzalez-Stegmaier R, Jorquera RA, Salinas E. Intersections between innate immune response and gastric cancer development. World J Gastroenterol 2023; 29:2222-2240. [PMID: 37124883 PMCID: PMC10134417 DOI: 10.3748/wjg.v29.i15.2222] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/07/2022] [Accepted: 03/13/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastric cancer (GC) is the fifth most commonly diagnosed malignancy. It has a reduced prevalence but has maintained its poor prognosis being the fourth leading cause of deaths related to cancer. The highest mortality rates occur in Asian and Latin American countries, where cases are usually diagnosed at advanced stages. Overall, GC is viewed as the consequence of a multifactorial process, involving the virulence of the Helicobacter pylori (H. pylori) strains, as well as some environmental factors, dietary habits, and host intrinsic factors. The tumor microenvironment in GC appears to be chronically inflamed which promotes tumor progression and reduces the therapeutic opportunities. It has been suggested that inflammation assessment needs to be measured qualitatively and quantitatively, considering cell-infiltration types, availability of receptors to detect damage and pathogens, and presence or absence of aggressive H. pylori strains. Gastrointestinal epithelial cells express several Toll-like receptors and determine the first defensive line against pathogens, and have been also described as mediators of tumorigenesis. However, other molecules, such as cytokines related to inflammation and innate immunity, including immune checkpoint molecules, interferon-gamma pathway and NETosis have been associated with an increased risk of GC. Therefore, this review will explore innate immune activation in the context of premalignant lesions of the gastric epithelium and established gastric tumors.
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Affiliation(s)
- Franz Villarroel-Espindola
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Troy Ejsmentewicz
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roxana Gonzalez-Stegmaier
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Roddy A Jorquera
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
| | - Esteban Salinas
- Translational Medicine Unit, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago 7500000, Metropolitan region, Chile
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Sun H, Li Y, Zhang P, Xing H, Zhao S, Song Y, Wan D, Yu J. Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives. Biomark Res 2022; 10:89. [PMID: 36476317 PMCID: PMC9727882 DOI: 10.1186/s40364-022-00436-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022] Open
Abstract
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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Affiliation(s)
- Hao Sun
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yingmei Li
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Peng Zhang
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Haizhou Xing
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Song Zhao
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yongping Song
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Dingming Wan
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Jifeng Yu
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
- Henan International Joint Laboratory of Nuclear Protein Gene Regulation, Henan University College of Medicine, Kaifeng, 475004 Henan China
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Expression of TLR1, TLR3 and TLR7 genes remarkably down-regulated from erosion to peptic ulcer and gastric cancer development. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Zhao W, Liu M, Zhang M, Wang Y, Zhang Y, Wang S, Zhang N. Effects of Inflammation on the Immune Microenvironment in Gastric Cancer. Front Oncol 2021; 11:690298. [PMID: 34367971 PMCID: PMC8343517 DOI: 10.3389/fonc.2021.690298] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/01/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Chronic inflammation and immune cell dysfunction in the tumor microenvironment are key factors in the development and progression of gastric tumors. However, inflammation-related genes associated with gastric cancer prognosis and their relationship with the expression of immune genes are not fully understood. METHOD In this study, we established an inflammatory response model score called "Riskscore", based on differentially expressed genes in gastric cancer. We used Survival and Survminer packages in R to analyze patient survival and prognosis in risk groups. The survival curve was plotted using the Kaplan-Meier method, and the log-rank test was used to assess statistical significance, and we performed the ROC analysis using the R language package to analyze the 1-, 3-, and 5-year survival of patients in the GEO and TCGA databases. Single-factor and multi-factor prognostic analyses were carried out for age, sex, T, N, M, and risk score. Pathway enrichment analysis indicated immune factor-related pathway enrichment in both patient groups. Next, we screened for important genes that are involved in immune cell regulation. Finally, we created a correlation curve to explore the correlation between Riskscore and the expression of these genes. RESULTS The prognosis was significantly different between high- and low-risk groups, and the survival rate and survival time of the high-risk group were lower than those of the low-risk group. we found that the pathways related to apoptosis, hypoxia, and immunity were most enriched in the risk groups. we found two common tumor-infiltrating immune cell types (i.e., follicular helper T cells and resting dendritic cells) between the two risk groups and identified 10 genes that regulate these cells. Additionally, we found that these 10 genes are positively associated with the two risk groups. CONCLUSION Finally, a risk model of the inflammatory response in gastric cancer was established, and the inflammation-related genes used to construct the model were found to be directly related to immune infiltration. This model can improve the gastric cancer prognosis prediction. Our findings contribute to the development of immunotherapy for the treatment of gastric cancer patients.
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Affiliation(s)
- Weidan Zhao
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Mingqing Liu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Mingyue Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yachen Wang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yingli Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Shiji Wang
- Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, China
| | - Nan Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Gao Y, Zhao Q, Xiao M, Huang X, Wu X. A versatile photothermal vaccine based on acid-responsive glyco-nanoplatform for synergistic therapy of cancer. Biomaterials 2021; 273:120792. [PMID: 33872856 DOI: 10.1016/j.biomaterials.2021.120792] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 02/24/2021] [Accepted: 03/29/2021] [Indexed: 01/10/2023]
Abstract
The race is on for therapeutic agents that stop cancer. An effective vaccine offers a safe and promising approach for cancer immunotherapy. However, substantial barriers to immunotherapy in cancer vaccines include the low immunogenicity of cancer antigens and the immunosuppression commonly present in solid tumors, resulting in significant challenges for developing a clinically effective cancer vaccine. Here, the state of the art of synergistic therapy, which includes the photothermal effect combined with immunotherapy, was investigated to target tumors. For the first time, indocyanine green (ICG, referred to as I), imiquimod (R837, referred to as R) and a foreign cytotoxic T lymphocyte antigen peptide (CTL-Ap, referred to as Ap) with the sequence of SIINFEKL from ovalbumin (OVA) were encapsulated by acetalated dextran (AcDEX) to form nanoparticles (NPs) averaging 92 nm in diameter as an immunogen. Administration of the resulting multifunctional vaccine I-R-Ap-AcDEX NPs enhanced antitumor cytotoxic T lymphocyte (CTL) immunotherapy. On the one hand, subcutaneous immunization of the NPs allows foreign Ap to enter the major histocompatibility complex class I (MHC-I) cross-presentation pathway of antigen-presenting cells, thereby presenting Ap and eliciting high levels of Ap-specific CTLs. On the other hand, intratumor/intravenous injections of the NPs allow foreign Ap to enter tumor cells and present Ap through the MHC-I cross-presentation pathway. Ap-specific CTLs can kill Ap-presented tumor cells. Furthermore, the NPs generated near-infrared laser triggered the photothermal killing of tumor cells. To our knowledge, this is the first report of AcDEX NPs in antitumor photothermal therapy. Strikingly, systemic administration of the I-R-Ap-AcDEX NPs combined with near-infrared laser irradiation allowed for complete protection to mice from the tumors when applied to two non-OVA tumor models. This quite impressive result displays the great promise of synergistic therapy by the vaccine I-R-Ap-AcDEX NPs, an approach that harnesses the photothermal effect to boost antitumor immunotherapy.
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Affiliation(s)
- Yanan Gao
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, Qingdao, Shandong, 266237, China
| | - Qingyu Zhao
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, Qingdao, Shandong, 266237, China
| | - Min Xiao
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, Qingdao, Shandong, 266237, China; State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237, China
| | - Xuefei Huang
- Departments of Chemistry and Biomedical Engineering, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, 48824, United States
| | - Xuanjun Wu
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, Qingdao, Shandong, 266237, China; Suzhou Research Institute, Shandong University, Suzhou, Jiangsu, 215123, China.
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Cui L, Wang X, Zhang D. TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer. Front Cell Dev Biol 2021; 8:611444. [PMID: 33469538 PMCID: PMC7813757 DOI: 10.3389/fcell.2020.611444] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world, and the incidence of gastric cancer in Asia appears to increase in recent years. Although there is a lot of improvement in treatment approaches, the prognosis of GC is poor. So it is urgent to search for a novel and more effective treatment to improve the survival rate of patients. Both innate immunity and adaptive immunity are important in cancer. In the innate immune system, pattern recognition receptors (PRRs) activate immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs). Many studies have reported that TLRs are involved in the occurrence, development, and treatment of GC. Therefore, TLRs are potential targets for immunotherapy to gastric cancer. However, gastric cancer is a heterogeneous disorder, and TLRs function in GC is complex. TLRs agonists can be potentially used not only as therapeutic agents to treat gastric cancer but also as adjuvants in conjunction with other immunotherapies. They might provide a promising new target for GC treatment. In the review, we sort out the mechanism of TLRs involved in tumor immunity and summarize the current progress in TLRs-based therapeutic approaches and other immunotherapies in the treatment of GC.
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Affiliation(s)
- Lin Cui
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiuqing Wang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Texas A&M University, Houston, TX, United States
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Genetic variants in the regulation region of TLR4 reduce the gastric cancer susceptibility. Gene 2020; 767:145181. [PMID: 33007372 DOI: 10.1016/j.gene.2020.145181] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 08/30/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is one of the most common cancers diagnosed in China. It has been suggested that the genetic polymorphisms of Toll-like receptors (TLRs) might be in close relation to tumorigenesis and development of gastric cancer. In this study, we performed a case-control study to investigate the genetic polymorphisms of TLR3, 4, 5, 7 with the genetic susceptibility of gastric cancer. TLRs gene polymorphisms in 471 gastric cancer (GC) patients and 471 healthy controls were analyzed by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis or TaqMan assays. Odds ratio (OR) and its 95% confidence interval (95%CI) were used to evaluate the association of TLR4 variants with the GC risk via unconditional logistic regression. Our results suggested that variant genotypes of TLR4 rs7869402 (OR = 0.61, 95%CI = 0.40-0.92, P = 0.02) and TLR4 rs7873784 (OR = 0.17, 95%CI = 0.09-0.33, P < 0.01) gene polymorphisms reduced the risk of GC. Stratified analysis showed that rs7869402 T-containing genotype significantly decreased the susceptibility of GC among females (OR = 0.38, 95%CI = 0.16-0.91, P = 0.03), older subjects (OR = 0.48, 95%CI = 0.26-0.87, P = 0.02), non-smokers (OR = 0.41, 95%CI = 0.23-0.71, P < 0.01) and non-drinkers (OR = 0.58, 95%CI = 0.30-0.78, P < 0.01). In case of rs7873784 polymorphism, C-containing genotype reduced the risk of GC among males (OR = 0.08, 95%CI = 0.03-0.21, P < 0.01), but not among females (OR = 0.53, 95%CI = 0.22-1.27, P = 0.15). As to the other four SNPs (TLR3 rs5743303, TLR4 rs1927914, TLR5 rs1640816 and TLR7 rs3853839), no significant correlations were found to be related to the risk of gastric carcinoma. Our research demonstrated the significance of TLRs polymorphisms in decreasing the risk of GC.
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Kasurinen A, Hagström J, Laitinen A, Kokkola A, Böckelman C, Haglund C. Evaluation of toll-like receptors as prognostic biomarkers in gastric cancer: high tissue TLR5 predicts a better outcome. Sci Rep 2019; 9:12553. [PMID: 31467388 PMCID: PMC6715705 DOI: 10.1038/s41598-019-49111-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 08/12/2019] [Indexed: 12/24/2022] Open
Abstract
Toll-like receptors (TLRs), key proteins in innate immunity, appear to contribute to the inflammatory environment in carcinogenesis. Thus, we aimed to evaluate the tissue expressions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 as potential prognostic biomarkers in gastric cancer. We applied immunohistochemistry to study tissue samples from 313 patients operated on for gastric adenocarcinoma between 2000 and 2009 at the Department of Surgery, Helsinki University Hospital, Finland. A high expression of each TLR studied associated with the high expression of each other and with the intestinal-type histology (p < 0.001 for all). Five-year disease-specific survival among patients with a high TLR5 was 53.4% (95% confidence interval [CI] 43.4–63.4), whereas among patients with a low TLR5 it was 37.6% (95% CI 30.0–45.2; p = 0.014). A high TLR5 expression functioned as a marker of a better prognosis, particularly among those with a stage II disease (hazard ratio [HR] 0.33; 0.13–0.83; p = 0.019) or an intestinal-type cancer (HR 0.58; 95% CI 0.34–0.98; p = 0.043). In this study we show, for the first time, that a high TLR5 tissue expression may identify gastric cancer patients with a better prognosis, particularly among those with a stage II disease or an intestinal-type cancer.
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Affiliation(s)
- Aaro Kasurinen
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.
| | - Jaana Hagström
- Department of Pathology and Oral Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Alli Laitinen
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Arto Kokkola
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Camilla Böckelman
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Gupta CL, Babu Khan M, Ampasala DR, Akhtar S, Dwivedi UN, Bajpai P. Pharmacophore-based virtual screening approach for identification of potent natural modulatory compounds of human Toll-like receptor 7. J Biomol Struct Dyn 2019; 37:4721-4736. [PMID: 30661449 DOI: 10.1080/07391102.2018.1559098] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Toll-like receptor 7 (TLR7) is a transmembrane glycoprotein playing very crucial role in the signaling pathways involved in innate immunity and has been demonstrated to be useful in fighting against infectious disease by recognizing viral ssRNA & specific small molecule agonists. In order to find novel human TLR7 (hTLR7) modulators, computational ligand-based pharmacophore modeling approach was used to identify the molecular chemical features required for the modulation of hTLR7 protein. A training set of 20 TLR7 agonists with their known experimental activity was used to create pharmacophore model using 3D-QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio. The best developed hypothesis consists of four pharmacophoric features namely, one hydrogen bond donor (HBD), one ring aromatic (RA), and two hydrophobic (HY) character. The developed hypothesis was then validated by different methods such as cost analysis, test set method, and Fischer's test method for consistency. Hence, this validated model was further employed for screening of natural hit compounds from InterBioScreen Natural product database, consisting of more than 60,000 natural compounds and derivatives. The screened hit compounds were subsequently filtered by Lipinski's rule of 5, ADME and toxicity parameters and molecular docking studies to remove the false positive rates. Finally, molecular docking analysis led to identification of the (3a'S,6a'R)-3'-(3,4-dihydroxybenzyl)-5'-(3,4-dimethoxyphenethyl)-5-ethyl-3',3a'-dihydro-2'H-spiro[indoline-3,1'-pyrrolo[3,4-c]pyrrole]-2,4',6'(5'H,6a'H)-trione (Compound ID: STOCK1N-65837) as potent hTLR7 modulator due to its better docking score and molecular interactions compared to other compounds. The result of virtual screening was further validated using molecular dynamics (MD) simulation analysis. Thus, a 30 ns MD simulation analysis revealed high stability and effective binding of STOCK1N-65837 within the binding site of hTLR7. Therefore, the present study provides confidence for the utility of the selected chemical feature based pharmacophore model to design novel TLR7 modulators with desired biological activity.
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Affiliation(s)
- Chhedi Lal Gupta
- Institute for Development of Advanced computing, ONGC Centre for Advanced studies, University of Lucknow , Lucknow , UP , India.,Molecular Immunology Laboratory, Department of Biosciences, Integral University , Lucknow , UP , India
| | - Mohd Babu Khan
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University , Puducherry , India
| | - Dinakara Rao Ampasala
- Centre for Bioinformatics, School of Life Sciences, Pondicherry University , Puducherry , India
| | - Salman Akhtar
- Department of Bioengineering, Integral University , Lucknow , UP , India
| | - Upendra Nath Dwivedi
- Institute for Development of Advanced computing, ONGC Centre for Advanced studies, University of Lucknow , Lucknow , UP , India.,Department of Biochemistry, Centre of Excellence in Bioinformatics, Bioinformatics Infrastructure Facility, University of Lucknow , Lucknow , UP , India
| | - Preeti Bajpai
- Molecular Immunology Laboratory, Department of Biosciences, Integral University , Lucknow , UP , India
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