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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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2
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Jia G, He P, Dai T, Goh D, Wang J, Sun M, Wee F, Li F, Lim JCT, Hao S, Liu Y, Lim TKH, Ngo NT, Tao Q, Wang W, Umar A, Nashan B, Zhang Y, Ding C, Yeong J, Liu L, Sun C. Spatial immune scoring system predicts hepatocellular carcinoma recurrence. Nature 2025; 640:1031-1041. [PMID: 40074893 DOI: 10.1038/s41586-025-08668-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 01/17/2025] [Indexed: 03/14/2025]
Abstract
Given the high recurrence rates of hepatocellular carcinoma (HCC) post-resection1-3, improved early identification of patients at high risk for post-resection recurrence would help to improve patient outcomes and prioritize healthcare resources4-6. Here we observed a spatial and HCC recurrence-associated distribution of natural killer (NK) cells in the invasive front and tumour centre from 61 patients. Using extreme gradient boosting and inverse-variance weighting, we developed the tumour immune microenvironment spatial (TIMES) score based on the spatial expression patterns of five biomarkers (SPON2, ZFP36L2, ZFP36, VIM and HLA-DRB1) to predict HCC recurrence risk. The TIMES score (hazard ratio = 88.2, P < 0.001) outperformed current standard tools for patient risk stratification including the TNM and BCLC systems. We validated the model in 231 patients from five multicentred cohorts, achieving a real-world accuracy of 82.2% and specificity of 85.7%. The predictive power of these biomarkers emerged through the integration of their spatial distributions, rather than individual marker expression levels alone. In vivo models, including NK cell-specific Spon2-knockout mice, revealed that SPON2 enhances IFNγ secretion and NK cell infiltration at the invasive front. Our study introduces TIMES, a publicly accessible tool for predicting HCC recurrence risk, offering insights into its potential to inform treatment decisions for early-stage HCC.
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MESH Headings
- Animals
- Female
- Humans
- Male
- Mice
- Middle Aged
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Cohort Studies
- Extracellular Matrix Proteins/genetics
- Extracellular Matrix Proteins/deficiency
- Extracellular Matrix Proteins/metabolism
- Interferon-gamma/metabolism
- Killer Cells, Natural/immunology
- Killer Cells, Natural/cytology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Mice, Knockout
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/diagnosis
- Neoplasm Recurrence, Local/pathology
- Reproducibility of Results
- Tumor Microenvironment
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Affiliation(s)
- Gengjie Jia
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
- Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
| | - Peiqi He
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Tianli Dai
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Denise Goh
- Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Jiabei Wang
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Mengyuan Sun
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Felicia Wee
- Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Fuling Li
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Jeffrey Chun Tatt Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore
| | - Shuxia Hao
- Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
| | - Yao Liu
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Tony Kiat Hon Lim
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Duke-NUS Medical School, Singapore, Singapore
| | | | - Qingping Tao
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China
| | - Ahitsham Umar
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Björn Nashan
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China
| | - Yongchang Zhang
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Central South University, Changsha, China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Fudan University, Shanghai, China
| | - Joe Yeong
- Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
- Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
- Cancer Science Institute, National University of Singapore, Singapore, Singapore.
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China.
| | - Cheng Sun
- Department of Hepatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, China.
- Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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Sato Y, Yamaya A, Sonoda K, Wakita A, Nagaki Y, Sasamori R, Sasaki Y, Yoneya T, Nozaki S, Takahashi T, Matsumoto M, Seya T, Imai K. Poly(I:C) signaling induces robust CXCL10 production and apoptosis in human esophageal squamous cell carcinoma cells. Hum Cell 2025; 38:63. [PMID: 40029556 PMCID: PMC11876272 DOI: 10.1007/s13577-025-01191-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/20/2025] [Indexed: 03/05/2025]
Abstract
We previously reported that high tumoral expression of Toll-like receptor 3 (TLR3) and CXCL10, a member of the CXC chemokine family, was an independent positive prognostic factor in patients with advanced thoracic esophageal squamous cell carcinoma (ESCC). However, the direct relationships between TLR3 and CXCL10 in ESCC cells was not fully understood. Here, we analyzed TLR3 mRNA and protein expression in two ESCC lines (TE8 and KYSE180) and one esophageal adenocarcinoma (EAC) line (OE19). We also assessed the effect of the TLR3 agonist poly(I:C) on production of downstream adapter proteins and cytokines, including CXCL10, and further tested its effects on cell viability and caspase 3/7 activity with and without siRNA-induced knockdown of TLR3 and the TICAM-1 or MAVS adapter protein. Both ESCC lines, but not the EAC line, showed high expression of TLR3 mRNA and protein. TICAM-1 and MAVS were also expressed, and their knockdown suppressed responsiveness to poly(I:C) in the ESCC lines. Poly(I:C) induced strong CXCL10 production, resulting in significantly upregulated caspase3/7 activity and downregulated cell proliferation in both ESCC lines but not the EAC line. The effect of poly(I:C) on CXCL10 production was attenuated after transfecting the cells with siRNAs targeting TICAM-1 or MAVS. TLR3 is thus highly expressed in ESCC cells, where it induces strong CXCL10 production and significantly upregulates caspase3/7 activity and downregulates cell proliferation. TLR3 signaling and the resultant downstream CXCL10 production have the potential to serve as useful prognostic markers and therapeutic targets for the treatment of ESCC.
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Affiliation(s)
- Yusuke Sato
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan.
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan.
| | - Akari Yamaya
- Nebuta Research Institute for Life Sciences, Aomori University, Aomori, 030-0943, Japan
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, 011-0020, Japan
| | - Kento Sonoda
- Nebuta Research Institute for Life Sciences, Aomori University, Aomori, 030-0943, Japan
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, 011-0020, Japan
| | - Akiyuki Wakita
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Yushi Nagaki
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Ryohei Sasamori
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Yoshihiro Sasaki
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Takatoshi Yoneya
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Shu Nozaki
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Tsukasa Takahashi
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
| | - Misako Matsumoto
- Nebuta Research Institute for Life Sciences, Aomori University, Aomori, 030-0943, Japan
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, 011-0020, Japan
| | - Tsukasa Seya
- Nebuta Research Institute for Life Sciences, Aomori University, Aomori, 030-0943, Japan
- Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Sapporo, 011-0020, Japan
| | - Kazuhiro Imai
- Department of Esophageal Surgery, Akita University Hospital, Akita, 010-8543, Japan
- Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, 010-8543, Japan
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4
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Liu R, Liu Y, Huang W, Chen P, Cheng Y. An anoikis-related signature predicts prognosis and immunotherapy response in gastrointestinal cancers. Front Immunol 2025; 16:1477913. [PMID: 39981252 PMCID: PMC11839610 DOI: 10.3389/fimmu.2025.1477913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 01/21/2025] [Indexed: 02/22/2025] Open
Abstract
Background Gastrointestinal (GI) cancers have high incidence rates and mortality rates. Anoikis is a special type of cell apoptosis, and anoikis resistance has been reported to be associated with tumor malignancy. We aimed to explore the roles of anoikis-related genes (ARGs) in the GI cancer prognosis. Methods We extracted RNA sequencing and clinical data from The Cancer Genome Atlas and Gene Expression Omnibu databases for patients with esophageal cancer, gastric cancer, colon cancer and rectal cancer and identified ARGs from GeneCards and Harmonizome. Anoikis-related patterns were identified via unsupervised clustering analysis. We constructed a prognostic signature (Anoscore) based on prognostic ARGs through univariate, LASSO, and multivariate Cox regression analyses. The model was validated and evaluated using Kaplan-Meier analysis, receiver operating characteristic curves, univariate Cox regression analysis, multivariate Cox regression analysis, column charts, and calibration curves. We also performed a single-cell sequencing analysis of candidate genes via TISCH2. A correlation analysis between the Anoscore, the tumor microenvironment and drug sensitivity was conducted in GI cancers. The expression and function of some candidate genes were validated in vitro. Results In terms of prognostic ARGs, two anoikis-related patterns, ARG clusters A and B, were identified. ARG cluster B had a worse prognosis than did ARG cluster A. Subsequently, the Anoscore was developed as an independent prognostic factor. It demonstrated the robust predictive capability for the prognosis of patients with GI cancers. Notably, patients with high Anoscores exhibited poor outcomes. In addition, we established a nomogram (Ano-nomogram) based on the Anoscore and clinicopathological factors of patients to predict the 3-year and 5-year survival probabilities. Moreover, patients with high Anoscores had higher levels of immune cell infiltration and higher immune checkpoint expression. The drug sensitivity analysis revealed that patients with high or low Anoscores were sensitive to different chemotherapies and targeted drugs. S100A11 and TLR3, representative candidate genes, exhibited different expression patterns and biological functions. Conclusion This study highlighted the significant potential of the Anoscore in predicting prognosis and guiding the selection of personalized therapeutic regimens for patients with GI cancers.
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Affiliation(s)
- Ruyi Liu
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Malignant Tumor Precision Treatment, Jinan, China
- Shandong Provincial Engineering Research Center for Tumor Precision Treatment, Jinan, China
- Cancer Institute of Shandong University, Jinan, China
- Neutron Medical Center, Qilu Hospital of Shandong University, Jinan, China
| | - Yuchen Liu
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Malignant Tumor Precision Treatment, Jinan, China
- Shandong Provincial Engineering Research Center for Tumor Precision Treatment, Jinan, China
- Cancer Institute of Shandong University, Jinan, China
- Neutron Medical Center, Qilu Hospital of Shandong University, Jinan, China
| | - Weicheng Huang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Malignant Tumor Precision Treatment, Jinan, China
- Shandong Provincial Engineering Research Center for Tumor Precision Treatment, Jinan, China
- Cancer Institute of Shandong University, Jinan, China
- Neutron Medical Center, Qilu Hospital of Shandong University, Jinan, China
| | - Pengxiang Chen
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Malignant Tumor Precision Treatment, Jinan, China
- Shandong Provincial Engineering Research Center for Tumor Precision Treatment, Jinan, China
- Cancer Institute of Shandong University, Jinan, China
- Neutron Medical Center, Qilu Hospital of Shandong University, Jinan, China
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Malignant Tumor Precision Treatment, Jinan, China
- Shandong Provincial Engineering Research Center for Tumor Precision Treatment, Jinan, China
- Cancer Institute of Shandong University, Jinan, China
- Neutron Medical Center, Qilu Hospital of Shandong University, Jinan, China
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Chung KY, Kim S, Yoon HT, Kwon SH, Park HS, Im JP, Kim JS, Kim JW, Han YM, Koh SJ. Toll-like receptor 3 signaling attenuated colitis-associated cancer development in mice. Sci Rep 2024; 14:30308. [PMID: 39639064 PMCID: PMC11621332 DOI: 10.1038/s41598-024-76954-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 10/18/2024] [Indexed: 12/07/2024] Open
Abstract
Inflammatory bowel disease is associated with a high risk of colitis-associated cancer (CAC). We evaluated the role of TLR3 in CAC using a murine model. Wild-type (WT) and TLR3-knockout (TLR3-/-) mice received azoxymethane (AOM) 12.5 mg/kg intraperitoneally on day zero, followed by three cycles of 2% dextran sulfate sodium (DSS) for five days and free water for two weeks. We evaluated clinical indices, such as weight change, colon length, histological severity of colitis, and tumor number. We performed immunofluorescence assays for phospho-IκB kinase and β-catenin in colon tissues. To elucidate the antitumorigenic mechanism of TLR3 signaling, we injected poly(I: C) or phosphate-buffered saline intraperitoneally into an AOM/DSS-induced tumorigenesis model in WT mice. We also evaluate the direct antitumor effect of TLR signaling in AOM-treated WT and TLR3-/- mice without DSS. TLR3 deficiency increased tumor burden and colitis severity in the colon tissue than in the WT mice. β-catenin immunoreactivity was higher in TLR3-/- mice, while phospho-IκB kinase expression was similar. TLR3 activation by poly(I: C) did not reduce tumor burden in WT mice, but long-term AOM administration without DSS significantly increased tumor burden in TLR3-/- mice. TLR3 signaling attenuates CAC development, suggesting it may be a target for preventing CAC in inflammatory bowel disease.
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Affiliation(s)
- Kee Young Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Seulji Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Tae Yoon
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - So Hyun Kwon
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Sun Park
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Dermatology, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Jong Pil Im
- Division of Gastroenterology, Department of Internal medicine, Seoul National University Hospital, Seoul, Korea
| | - Joo Sung Kim
- Division of Gastroenterology, Department of Internal medicine, Seoul National University Hospital, Seoul, Korea
| | - Ji Won Kim
- Division of Gastroenterology, Department of Internal medicine, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Yoo Min Han
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Seong-Joon Koh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
- Laboratory of Intestinal Mucosa and Skin Immunology, Seoul National University College of Medicine, Seoul, Korea.
- Division of Gastroenterology, Department of Internal medicine, Seoul National University Hospital, Seoul, Korea.
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Qiu L, Ji H, Wang K, Liu W, Huang Q, Pan X, Ye H, Li Z, Chen G, Xing X, Dong X, Tang R, Xu H, Liu J, Cai Z, Liu X. TLR3 activation enhances abscopal effect of radiotherapy in HCC by promoting tumor ferroptosis. EMBO Mol Med 2024; 16:1193-1219. [PMID: 38671318 PMCID: PMC11098818 DOI: 10.1038/s44321-024-00068-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8+ T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.
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Affiliation(s)
- Liman Qiu
- College of Chemical Engineering, Fuzhou University, Fuzhou, P. R. China
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Hongbing Ji
- Radiotherapy Department, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Kai Wang
- Radiotherapy Department, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Wenhan Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Qizhen Huang
- Radiotherapy Department, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Xinting Pan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Honghao Ye
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Zhenli Li
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Geng Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Xiaohua Xing
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Xiuqing Dong
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Ruijing Tang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Haipo Xu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
| | - Jingfeng Liu
- College of Chemical Engineering, Fuzhou University, Fuzhou, P. R. China
| | - Zhixiong Cai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China.
| | - Xiaolong Liu
- College of Chemical Engineering, Fuzhou University, Fuzhou, P. R. China.
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China.
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Hu A, Sun L, Lin H, Liao Y, Yang H, Mao Y. Harnessing innate immune pathways for therapeutic advancement in cancer. Signal Transduct Target Ther 2024; 9:68. [PMID: 38523155 PMCID: PMC10961329 DOI: 10.1038/s41392-024-01765-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/18/2024] [Accepted: 02/03/2024] [Indexed: 03/26/2024] Open
Abstract
The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.
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Affiliation(s)
- Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Li Sun
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Yuheng Liao
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, P.R. China
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
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Reghu G, Vemula PK, Bhat SG, Narayanan S. Harnessing the innate immune system by revolutionizing macrophage-mediated cancer immunotherapy. J Biosci 2024; 49:63. [PMID: 38864238 PMCID: PMC11286319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/18/2024] [Accepted: 02/03/2024] [Indexed: 06/13/2024]
Abstract
Immunotherapy is a promising and safer alternative to conventional cancer therapies. It involves adaptive T-cell therapy, cancer vaccines, monoclonal antibodies, immune checkpoint blockade (ICB), and chimeric antigen receptor (CAR) based therapies. However, most of these modalities encounter restrictions in solid tumours owing to a dense, highly hypoxic and immune-suppressive microenvironment as well as the heterogeneity of tumour antigens. The elevated intra-tumoural pressure and mutational rates within fastgrowing solid tumours present challenges in efficient drug targeting and delivery. The tumour microenvironment is a dynamic niche infiltrated by a variety of immune cells, most of which are macrophages. Since they form a part of the innate immune system, targeting macrophages has become a plausible immunotherapeutic approach. In this review, we discuss several versatile approaches (both at pre-clinical and clinical stages) such as the direct killing of tumour-associated macrophages, reprogramming pro-tumour macrophages to anti-tumour phenotypes, inhibition of macrophage recruitment into the tumour microenvironment, novel CAR macrophages, and genetically engineered macrophages that have been devised thus far. These strategies comprise a strong and adaptable macrophage-toolkit in the ongoing fight against cancer and by understanding their significance, we may unlock the full potential of these immune cells in cancer therapy.
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Affiliation(s)
- Gayatri Reghu
- Department of Biotechnology, Cochin University of Science and Technology, Kochi 682 022, India
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Chandrasekar SA, Palaniyandi T, Parthasarathy U, Surendran H, Viswanathan S, Wahab MRA, Baskar G, Natarajan S, Ranjan K. Implications of Toll-like receptors (TLRs) and their signaling mechanisms in human cancers. Pathol Res Pract 2023; 248:154673. [PMID: 37453359 DOI: 10.1016/j.prp.2023.154673] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Most essential pattern-recognition receptors regulating innate immune functions are toll-like receptors (TLRs). TLRs are characterized by lack of concurrent epithelial markers and are typically identified by their gene expressions. One major mechanism by which TLRs generate their effector functions is by triggering inflammatory responses. Activation of TLRs can impact initiation, advancement, and control of cancers by regulating the inflammatory microenvironment. Several TLRs have been implicated in human cancers and some of them are identified as cancer biomarkers as well; for example, TLRs 2, 3, 5 are expressed more frequently in most cancers. Knowing the upregulation and downregulation of the TLR genes in human cancers will be useful for the development of newer therapeutic targets which can disrupt the pathways associated with such deregulation. We present here the various TLRs and their functions in human lung, gastric, breast, prostate, oral, ovarian, colorectal, cervical, esophageal, bladder and hepatic cancers.
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Affiliation(s)
- Saran Aravinda Chandrasekar
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India; Department of Biomedical, School of Electronics Engineering (SENSE), VIT(Vellore Institute of Technology), Vellore 632014, India
| | - Thirunavukkarasu Palaniyandi
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India; Department of Anatomy, Biomedical Research Unit and Laboratory Animal Centre, Saveetha Dental College and Hospital, SIMATS, Saveetha University, Chennai, India.
| | - Udhayakumar Parthasarathy
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Hemapreethi Surendran
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Sandhiya Viswanathan
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Mugip Rahaman Abdul Wahab
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Gomathy Baskar
- Department of Biotechnology, Dr.MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
| | - Sudhakar Natarajan
- Department of virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis (NIRT), Chetpet, Chennai 600031, Tamil Nadu, India
| | - Kishu Ranjan
- Department of Pathology, School of Medicine, Yale University, New Haven 06520, USA
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10
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Butkowsky C, Aldor N, Poynter SJ. Toll‑like receptor 3 ligands for breast cancer therapies (Review). Mol Clin Oncol 2023; 19:60. [PMID: 37424627 PMCID: PMC10326562 DOI: 10.3892/mco.2023.2656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/31/2023] [Indexed: 07/11/2023] Open
Abstract
Breast cancer is the most common cause of cancer worldwide and is the leading cause of mortality for women across most of the world. Immunotherapy is a burgeoning area of cancer treatment, including for breast cancer; these are therapies that harness the power of the immune system to clear cancerous cells. Toll-like receptor 3 (TLR3) is an RNA receptor found in the endosome, and ligands that bind to TLR3 are currently being tested for their efficacy as breast cancer immunotherapeutics. The current review introduces TLR3 and the role of this receptor in breast cancer, and summarizes data on the potential use of TLR3 ligands, mainly polyinosinic:polycytidylic acid and its derivatives, as breast cancer monotherapies or, more commonly, as combination therapies with chemotherapies, other immunotherapies and cancer vaccines. The current state of TLR3 ligand breast cancer therapy research is summarized by reporting on past and current clinical trials, and notable preliminary in vitro studies are discussed. In conclusion, TLR3 ligands have robust potential in anticancer applications as innate immune stimulants, and further studies combined with innovative technologies, such as nanoparticles, may contribute to their success.
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Affiliation(s)
- Carly Butkowsky
- Department of Health Sciences, Faculty of Science, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada
| | - Natalie Aldor
- Department of Health Sciences, Faculty of Science, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada
| | - Sarah J. Poynter
- Department of Health Sciences, Faculty of Science, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada
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Haroun R, Naasri S, Oweida AJ. Toll-Like Receptors and the Response to Radiotherapy in Solid Tumors: Challenges and Opportunities. Vaccines (Basel) 2023; 11:vaccines11040818. [PMID: 37112730 PMCID: PMC10146579 DOI: 10.3390/vaccines11040818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 04/05/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Toll-like receptors (TLRs) are indispensable for the activation, maintenance and halting of immune responses. TLRs can mediate inflammation by recognizing molecular patterns in microbes (pathogen-associated molecular patterns: PAMPs) and endogenous ligands (danger-associated molecular patterns: DAMPs) released by injured or dead cells. For this reason, TLR ligands have attracted much attention in recent years in many cancer vaccines, alone or in combination with immunotherapy, chemotherapy and radiotherapy (RT). TLRs have been shown to play controversial roles in cancer, depending on various factors that can mediate tumor progression or apoptosis. Several TLR agonists have reached clinical trials and are being evaluated in combination with standard of care therapies, including RT. Despite their prolific and central role in mediating immune responses, the role of TLRs in cancer, particularly in response to radiation, remains poorly understood. Radiation is recognized as either a direct stimulant of TLR pathways, or indirectly through the damage it causes to target cells that subsequently activate TLRs. These effects can mediate pro-tumoral and anti-tumoral effects depending on various factors such as radiation dose and fractionation, as well as host genomic features. In this review, we examine how TLR signaling affects tumor response to RT, and we provide a framework for the design of TLR-based therapies with RT.
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Affiliation(s)
- Ryma Haroun
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1N 0Y8, Canada
| | - Sahar Naasri
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1N 0Y8, Canada
| | - Ayman J Oweida
- Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1N 0Y8, Canada
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12
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Zhou C, Yang ZF, Sun BY, Yi Y, Wang Z, Zhou J, Fan J, Gan W, Ren N, Qiu SJ. Lenvatinib Induces Immunogenic Cell Death and Triggers Toll-Like Receptor-3/4 Ligands in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:697-712. [PMID: 37138764 PMCID: PMC10149778 DOI: 10.2147/jhc.s401639] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/20/2023] [Indexed: 05/05/2023] Open
Abstract
Purpose Immunogenic cell death (ICD) is a cell death modality that plays a vital role in anticancer therapy. In this study, we investigated whether lenvatinib induces ICD in hepatocellular carcinoma and how it affects cancer cell behavior. Patients and Methods Hepatoma cells were treated with 0.5 μM lenvatinib for two weeks, and damage-associated molecular patterns were assessed using the expression of calreticulin, high mobility group box 1, and ATP secretion. Transcriptome sequencing was performed to investigate the effects of lenvatinib on hepatocellular carcinoma. Additionally, CU CPT 4A and TAK-242 were used to inhibit TLR3 and TLR4 expressions, respectively. Flow cytometry was used to assess PD-L1 expression. Kaplan-Meier and Cox regression models were applied for prognosis assessment. Results After treatment with lenvatinib, there was a significant increase in ICD-associated damage-associated molecular patterns, such as calreticulin on the cell membrane, extracellular ATP, and high mobility group box 1, in hepatoma cells. Following treatment with lenvatinib, there was a significant increase in the downstream immunogenic cell death receptors, including TLR3 and TLR4. Furthermore, lenvatinib increased the expression of PD-L1, which was later inhibited by TLR4. Interestingly, inhibiting TLR3 in MHCC-97H and Huh7 cells strengthened their proliferative capacity. Moreover, TLR3 inhibition was identified as an independent risk factor for overall survival and recurrence-free survival in patients with hepatocellular carcinoma. Conclusion Our study revealed that lenvatinib induced ICD in hepatocellular carcinoma and upregulated PD-L1 expression through TLR4 while promoting cell apoptosis through TLR3. Antibodies against PD-1/PD-L1 can enhance the efficacy of lenvatinib in the management of hepatocellular carcinoma.
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Affiliation(s)
- Cheng Zhou
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Yong Yi
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zheng Wang
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jia Fan
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Wei Gan
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Ning Ren
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Institute of Fudan Minhang Academic Health System & Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation & Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
- Correspondence: Shuang-Jian Qiu, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200030, People’s Republic of China, Tel +86 13916625289, Email
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Martín-Medina A, Cerón-Pisa N, Martinez-Font E, Shafiek H, Obrador-Hevia A, Sauleda J, Iglesias A. TLR/WNT: A Novel Relationship in Immunomodulation of Lung Cancer. Int J Mol Sci 2022; 23:6539. [PMID: 35742983 PMCID: PMC9224119 DOI: 10.3390/ijms23126539] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 02/07/2023] Open
Abstract
The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process.
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Affiliation(s)
- Aina Martín-Medina
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Noemi Cerón-Pisa
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Esther Martinez-Font
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Medical Oncology Department, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Hanaa Shafiek
- Chest Diseases Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
| | - Antònia Obrador-Hevia
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Molecular Diagnosis Unit, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Jaume Sauleda
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Department of Respiratory Medicine, Hospital Universitario Son Espases, 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Amanda Iglesias
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
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Jia Q, Chu H, Jin Z, Long H, Zhu B. High-throughput single-сell sequencing in cancer research. Signal Transduct Target Ther 2022; 7:145. [PMID: 35504878 PMCID: PMC9065032 DOI: 10.1038/s41392-022-00990-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/23/2022] [Accepted: 04/08/2022] [Indexed: 12/22/2022] Open
Abstract
With advances in sequencing and instrument technology, bioinformatics analysis is being applied to batches of massive cells at single-cell resolution. High-throughput single-cell sequencing can be utilized for multi-omics characterization of tumor cells, stromal cells or infiltrated immune cells to evaluate tumor progression, responses to environmental perturbations, heterogeneous composition of the tumor microenvironment, and complex intercellular interactions between these factors. Particularly, single-cell sequencing of T cell receptors, alone or in combination with single-cell RNA sequencing, is useful in the fields of tumor immunology and immunotherapy. Clinical insights obtained from single-cell analysis are critically important for exploring the biomarkers of disease progression or antitumor treatment, as well as for guiding precise clinical decision-making for patients with malignant tumors. In this review, we summarize the clinical applications of single-cell sequencing in the fields of tumor cell evolution, tumor immunology, and tumor immunotherapy. Additionally, we analyze the tumor cell response to antitumor treatment, heterogeneity of the tumor microenvironment, and response or resistance to immune checkpoint immunotherapy. The limitations of single-cell analysis in cancer research are also discussed.
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Affiliation(s)
- Qingzhu Jia
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.,Chongqing Key Laboratory of Immunotherapy, Chongqing, 400037, China
| | - Han Chu
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.,Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resources and Eco-Environment, College of Life Sciences, Sichuan University, Chengdu, 610064, China
| | - Zheng Jin
- Research Institute, GloriousMed Clinical Laboratory Co., Ltd, Shanghai, 201318, China
| | - Haixia Long
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China. .,Chongqing Key Laboratory of Immunotherapy, Chongqing, 400037, China.
| | - Bo Zhu
- Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China. .,Chongqing Key Laboratory of Immunotherapy, Chongqing, 400037, China.
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15
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Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 2021; 6:291. [PMID: 34344870 PMCID: PMC8333067 DOI: 10.1038/s41392-021-00687-0] [Citation(s) in RCA: 827] [Impact Index Per Article: 206.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 05/23/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.
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Affiliation(s)
- Danyang Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China.
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
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16
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Zhou J, Liu J, Xing H, Shen Y, Xie M, Chai J, Yang M. Implications of protein ubiquitination modulated by lncRNAs in gastrointestinal cancers. Biochem Pharmacol 2021; 188:114558. [PMID: 33844983 DOI: 10.1016/j.bcp.2021.114558] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/03/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023]
Abstract
Long non-coding RNAs (lncRNAs) are a class of RNA transcripts longer than 200 nucleotides and mostly cannot be translated into proteins. Next-generation transcriptome sequencing of various cell types has enabled the annotation of tens of thousands of lncRNAs in human genome. Varying levels of evidence supports the implications of lncRNAs in the onset and progression of cancers. Ubiquitin is an evolutionarily conserved protein and could post-translationally mark a number of proteins. The most important proteolytic role of ubiquitination is degradation of substrate proteins by the 26S proteasome. Compiling evidences demonstrated that lncRNAs are involved in the accurate execution of protein stability programs via the ubiquitin-proteasome system. In the current review, we systematically summarize the detailed mechanisms how lncRNAs modulate ubiquitination of target proteins, regulate cancerous signaling pathways and control tumorigenesis of gastrointestinal cancers. Although there are still considerable studies on unraveling the complicated interactions between lncRNAs and proteins, we believe that lncRNAs are promising but challenging molecules which may strongly facilitate precision cancer therapeutics in the future.
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Affiliation(s)
- Jianyuan Zhou
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jie Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Huaixin Xing
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Yue Shen
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Mengyu Xie
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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17
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Zheng X, Li S, Yang H. Roles of Toll-Like Receptor 3 in Human Tumors. Front Immunol 2021; 12:667454. [PMID: 33986756 PMCID: PMC8111175 DOI: 10.3389/fimmu.2021.667454] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/06/2021] [Indexed: 12/29/2022] Open
Abstract
Toll-like receptor 3 (TLR3) is an important member of the TLR family, which is an important group of pathogen-associated molecular patterns. TLR3 can recognize double-stranded RNA and induce activation of NF-κB and the production of type I interferons. In addition to its immune-associated role, TLR3 has also been detected in some tumors. However TLR3 can play protumor or antitumor roles in different tumors or cell lines. Here, we review the basic signaling associated with TLR3 and the pro- or antitumor roles of TLR3 in different types of tumors and discuss the possible reasons for the opposing roles of TLR3 in tumors.
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Affiliation(s)
- Xin Zheng
- Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Song Li
- Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hui Yang
- Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China
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18
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Hidalgo-Sastre A, Kuebelsbeck LA, Jochheim LS, Staufer LM, Altmayr F, Johannes W, Steiger K, Ronderos M, Hartmann D, Hüser N, Schmid RM, Holzmann B, von Figura G. Toll-like receptor 3 expression in myeloid cells is essential for efficient regeneration after acute pancreatitis in mice. Eur J Immunol 2021; 51:1182-1194. [PMID: 33521935 DOI: 10.1002/eji.202048771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 11/12/2020] [Accepted: 01/29/2021] [Indexed: 11/09/2022]
Abstract
Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3OFF ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3Mye ). Compared to WT mice, TLR3OFF mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3OFF mice. Importantly, the phenotype of TLR3OFF mice was rescued in TLR3Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death.
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Affiliation(s)
- Ana Hidalgo-Sastre
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Ludwig A Kuebelsbeck
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Leonie S Jochheim
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Lina M Staufer
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Felicitas Altmayr
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Widya Johannes
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Katja Steiger
- Technical University of Munich, School of Medicine, Department of Pathology, Munich, Germany
| | - Monica Ronderos
- Technical University of Munich, School of Medicine, Department of Pathology, Munich, Germany
| | - Daniel Hartmann
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Norbert Hüser
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Roland M Schmid
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Bernhard Holzmann
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Guido von Figura
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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19
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Roca Suarez AA, Testoni B, Baumert TF, Lupberger J. Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease. Front Immunol 2021; 11:624034. [PMID: 33613561 PMCID: PMC7892431 DOI: 10.3389/fimmu.2020.624034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- DNA, Viral/immunology
- Hepacivirus/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/mortality
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/mortality
- Hepatitis C, Chronic/pathology
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- RNA, Viral/immunology
- Signal Transduction/immunology
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Affiliation(s)
- Armando Andres Roca Suarez
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Thomas F. Baumert
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
- Institut Universitaire de France (IUF), Paris, France
| | - Joachim Lupberger
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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20
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Salazar AM, Celis E. Double-Stranded RNA Immunomodulators in Prostate Cancer. Urol Clin North Am 2021; 47:e1-e8. [PMID: 33446322 DOI: 10.1016/j.ucl.2020.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and antitumor responses that act at multiple stages of host defense. Their mechanisms of action and uses are beginning to be understood, alone, in combination with other therapeutics, or as novel PAMP-adjuvants providing the critical danger signal that has been missing from most cancer and other modern vaccines. Dose, timing, route of administration combinations, and other clinical variables can have a critical impact on immunogenicity. This article reviews advances in the use of polyinosinic-polycytidylic acid and derivatives, in particular poly-ICLC.
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Affiliation(s)
- Andres M Salazar
- Oncovir, Inc, 3203 Cleveland Avenue Northwest, Washington, DC 20008, USA.
| | - Esteban Celis
- Department of Medicine, Medical College of Georgia, Oncovir, Inc, 1410 Laney Walker Boulevard, CN4121, Augusta, GA 30912, USA
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21
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Guruprasad P, Lee YG, Kim KH, Ruella M. The current landscape of single-cell transcriptomics for cancer immunotherapy. J Exp Med 2021; 218:e20201574. [PMID: 33601414 PMCID: PMC7754680 DOI: 10.1084/jem.20201574] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/28/2020] [Accepted: 12/02/2020] [Indexed: 12/28/2022] Open
Abstract
Immunotherapies such as immune checkpoint blockade and adoptive cell transfer have revolutionized cancer treatment, but further progress is hindered by our limited understanding of tumor resistance mechanisms. Emerging technologies now enable the study of tumors at the single-cell level, providing unprecedented high-resolution insights into the genetic makeup of the tumor microenvironment and immune system that bulk genomics cannot fully capture. Here, we highlight the recent key findings of the use of single-cell RNA sequencing to deconvolute heterogeneous tumors and immune populations during immunotherapy. Single-cell RNA sequencing has identified new crucial factors and cellular subpopulations that either promote tumor progression or leave tumors vulnerable to immunotherapy. We anticipate that the strategic use of single-cell analytics will promote the development of the next generation of successful, rationally designed immunotherapeutics.
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Affiliation(s)
- Puneeth Guruprasad
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Yong Gu Lee
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Ki Hyun Kim
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Marco Ruella
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
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22
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Nersesian S, Schwartz SL, Grantham SR, MacLean LK, Lee SN, Pugh-Toole M, Boudreau JE. NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis. Transl Oncol 2020; 14:100930. [PMID: 33186888 PMCID: PMC7670197 DOI: 10.1016/j.tranon.2020.100930] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/20/2020] [Accepted: 10/23/2020] [Indexed: 01/03/2023] Open
Abstract
The immune landscape of a tumor is highly connected to patient prognosis and response to treatment, but little is known about how natural killer (NK) cells predict overall survival (OS) among patients with solid tumors. We present the first meta-analysis on NK cell infiltration into solid tumors as a prognostic indicator for OS, considering cancer types independently, and together. Samples were collected from 1973 to 2016 with results published between 1989 and 2020. From 53 studies, we found that NK cell infiltration corresponds with decreased risk of death (HR=0.34, 95% CI: 0.26-0.46; p<0.0001). Among studies that investigated the prognostic potential of NK cells in specific regions of the tumor, intraepithelial infiltration was better predictive of OS than NK infiltration in the tumor-adjacent stroma. Generally, NK cell infiltration is lower in advanced-stage and lower-grade tumors; nevertheless, it remains prognostically beneficial. This meta-analysis highlights an important prognostic role of NK cells in solid tumors, but exposes that few studies have considered the contributions of NK cells. Toward NK cell-based immunotherapies, it will be important to understand the conditions under which NK cells can be effective agents of tumor control.
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Affiliation(s)
- Sarah Nersesian
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Sarah L Schwartz
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Stephanie R Grantham
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Leah K MacLean
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Stacey N Lee
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Morgan Pugh-Toole
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Jeanette E Boudreau
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada.
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23
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Yoshida T, Miura T, Matsumiya T, Yoshida H, Morohashi H, Sakamoto Y, Kurose A, Imaizumi T, Hakamada K. Toll-Like Receptor 3 as a Recurrence Risk Factor and a Potential Molecular Therapeutic Target in Colorectal Cancer. Clin Exp Gastroenterol 2020; 13:427-438. [PMID: 33061521 PMCID: PMC7537813 DOI: 10.2147/ceg.s252157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose Colorectal cancer (CRC) often recurs after curative resection. Identification of major risk factors for CRC recurrence is important for effective prevention and treatment. In this study, we examined the potential relationship between CRC and TLR3 as this remains unclear. Patients and Methods Correlations between TLR3 immunostaining and clinicopathological factors and prognosis were examined in 50 samples that were randomly extracted from 264 patients with CRC from January 2010 to December 2011. Chemokines induced by TLR3 agonist stimulation were also examined using TLR3-positive human CRC cell lines. Furthermore, the association between TLR3 and chemokine expression was assessed by analyzing the immunohistochemistry of surgical specimens. Results Of the 50 patients, 14 (28%) were TLR3-negative. In the comparison of clinicopathological factors between the TLR3-negative and -positive groups, there were more lymph node metastasis-positive cases in the TLR3-negative group, and this difference was significant. Furthermore, there was no difference in overall survival rates between the two groups, but the 5-year recurrence-free survival (RFS) was significantly lower in the TLR3-negative group (46.2%) than in the TLR3-positive group (78.1%). Analysis of 5-year RFS using factors thought to be related to recurrence identified a high tumor budding and a TLR3-negative status as independent risk factors for recurrence. TLR3 activation of CRC cell lines induced expression of C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 5 (CCL5), and interleukin-8. The expressions of CCL2, CCL5, and IL-8 were observed in the TLR3-positive tumor cells of surgical specimens. Conclusion Non-expression of TLR3 in CRC cells was associated with lymph node metastasis and was an independent risk factor for recurrence. These results suggest that TLR3 may not only be used as a prognostic factor and a risk factor for recurrence, but further studies on the involvement of TLR3 with tumor growth may provide new therapeutic strategies.
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Affiliation(s)
- Tatsuya Yoshida
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takuya Miura
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tomoh Matsumiya
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hidemi Yoshida
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hajime Morohashi
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yoshiyuki Sakamoto
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Akira Kurose
- Department of Anatomic Pathology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tadaatsu Imaizumi
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
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24
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Sultan H, Salazar AM, Celis E. Poly-ICLC, a multi-functional immune modulator for treating cancer. Semin Immunol 2020; 49:101414. [PMID: 33011064 DOI: 10.1016/j.smim.2020.101414] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/22/2022]
Abstract
Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low rate of success can be attributed to 3 main barriers: 1) low frequency of anti-tumor specific T cells; 2) lack of infiltration of the anti-tumor specific T cells into the tumor parenchyma and 3) accumulation of highly suppressive cells in the tumor mass that inhibit the effector function of the anti-tumor specific T cells. Thus, the identification of immunomodulators that can increase the frequency and/or the infiltration of antitumor specific T cells while reducing the suppressive capacity of the tumor microenvironment is necessary to ensure the effectiveness of T cell immunotherapies. In this review, we discuss the potential of poly-ICLC as a multi-functional immune modulator for treating cancer and its impact on the 3 above mentioned barriers. We describe the unique capacity of poly-ICLC in stimulating 2 separate pattern recognition receptors, TLR3 and cytosolic MDA5 and the consequences of these activations on cytokines and chemokines production. We emphasize the role of poly-ICLC as an adjuvant in the setting of peptide-based cancer vaccines and in situ tumor vaccination by mimicking natural immune responses to infections. Finally, we summarize the impact of poly-ICLC in enhancing T infiltration into the tumor parenchyma and address the implication of this finding in the clinic.
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Affiliation(s)
- Hussein Sultan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
| | | | - Esteban Celis
- Cancer Immunology Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
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25
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Abstract
BACKGROUND Transarterial radioembolization (TARE) is a locoregional minimally invasive therapeutic strategy to treat primary and secondary hepatic neoplasia. AIM The objective was to assess TARE-induced immuno-oncological effects and its perspective for potential therapy improvement by using a combinatory strategy with immune checkpoint inhibitors (ICI). RESULTS Yttrium-90 (90Y) TARE is used in patients with persisting liver function as the first- and second-line treatment for cholangiocarcinoma and hepatocellular carcinoma and chemotherapy refractory liver metastasis of different primaries. Combination therapy with 90Y TARE and ICI may synergistically improve antitumoral immunity and patient outcome. Currently, there are no clinical studies with published data regarding this combination therapy and the subsequently induced immunological effects. Clinical data on other isotopes, e.g., holmium-166 (166Ho), are also lacking. CONCLUSION The clinical evidence of combined treatment with TARE and ICI must be considerably improved. This innovative therapy concept must be studied in new trials assessing the immunological data, including cellular phenotypes, activation, functions, and biomarkers. This may provide valid, sensitive, and specific models in order to evaluate the optimal therapy concept and/or the therapy combination for the best patient outcome.
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Affiliation(s)
- Borna Relja
- Experimentelle Radiologie, Otto-von-Guericke Universität, Leipziger Straße 44, 39120, Magdeburg, Deutschland.
| | - Maciej Pech
- Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Leipziger Straße 44, 39120, Magdeburg, Deutschland.
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26
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Le Naour J, Galluzzi L, Zitvogel L, Kroemer G, Vacchelli E. Trial watch: TLR3 agonists in cancer therapy. Oncoimmunology 2020; 9:1771143. [PMID: 32934877 PMCID: PMC7466857 DOI: 10.1080/2162402x.2020.1771143] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells. These aspects of TLR3 biology have supported the development of various agonists for use as stand-alone agents or combined with other therapeutic modalities in cancer patients. Here, we review recent preclinical and clinical advances in the development of TLR3 agonists for oncological disorders. Abbreviations cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; dsRNA, double-stranded RNA; FLT3LG, fms-related receptor tyrosine kinase 3 ligand; HNSCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; ISV, in situ vaccine; MUC1, mucin 1, cell surface associated; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic acid; TLR, Toll-like receptor.
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Affiliation(s)
- Julie Le Naour
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université De Paris, Sorbonne Université, INSERM U1138, Centre De Recherche Des Cordeliers, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Faculty of Medicine Kremlin Bicêtre, Université Paris Sud, Paris Saclay, Kremlin Bicêtre, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, New York, NY, USA.,Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.,Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.,Université De Paris, Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France.,Equipe Labellisée Ligue Contre Le Cancer, INSERM, Villejuif, France.,Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France
| | - Guido Kroemer
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université De Paris, Sorbonne Université, INSERM U1138, Centre De Recherche Des Cordeliers, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France.,Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.,AP-HP, Hôpital Européen Georges Pompidou, Paris, France.,Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.,Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Erika Vacchelli
- Equipe Labellisée Par La Ligue Contre Le Cancer, Université De Paris, Sorbonne Université, INSERM U1138, Centre De Recherche Des Cordeliers, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.,Gustave Roussy Cancer Campus, Villejuif, France
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27
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Salem ML, El-Naggar SA, Mobasher MA, Elgharabawy RM. The Toll-Like Receptor 3 Agonist Polyriboinosinic Polyribocytidylic Acid Increases the Numbers of NK Cells with Distinct Phenotype in the Liver of B6 Mice. J Immunol Res 2020; 2020:2489407. [PMID: 32211442 PMCID: PMC7077049 DOI: 10.1155/2020/2489407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 02/15/2020] [Indexed: 02/07/2023] Open
Abstract
One of the activating factors of the cells of the innate immune system is the agonists of toll-like receptors (TLRs). Our earlier publications detailed how poly(I:C), a TLR3 agonist, elevates the NK cell population and the associated antigen-specific CD8+ T cell responses. This study involved a single treatment of the B6 mice with poly(I:C) intraperitoneally. To perform a detailed phenotypic analysis, mononuclear cells were prepared from each of the liver, peripheral blood, and spleen. These cells were then examined for their NK cell population by flow cytometric analysis following cell staining with indicated antibodies. The findings of the study showed that the NK cell population of the liver with an NK1.1highCD11bhighCD11chigh B220+Ly6G- phenotype was elevated following the treatment with poly(I:C). In the absence of CD11b molecule (CR3-/- mice), poly(I:C) can still increase the remained numbers of NK cells with NK1.1+CD11b- and NK1.1+Ly6G- phenotypes in the liver while their numbers in the blood decrease. After the treatment with anti-AGM1 Ab, which induced depletion of NK1.1+CD11b+ cells and partial depletion of CD3+NK1.1+ and NK1.1+CD11b- cell populations, poly(I:C) normalized the partial decreases in the numbers of NK cells concomitant with increased numbers of NK1.1-CD11b+ cell population in both liver and blood. Regarding mice with a TLR3-/- phenotype, their injection with poly(I:C) resulted in the partial elevation in the NK cell population as compared to wild-type B6 mice. To summarise, the TLR3 agonist poly(I:C) results in the elevation of a subset of liver NK cells expressing the two myeloid markers CD11c and CD11b. The effect of poly(I:C) on NK cells is partially dependent on TLR3 and independent of the presence of CD11b.
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Affiliation(s)
- Mohamed L. Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
- Center of Excellence in Cancer Research, New Tanta University Teaching Hospital, Tanta University, Egypt
| | - Sabry A. El-Naggar
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
- Center of Excellence in Cancer Research, New Tanta University Teaching Hospital, Tanta University, Egypt
| | - Maysa A. Mobasher
- Biochemistry Division, Department of Pathology, College of Medicine, Jouf University, Sakakah, Saudi Arabia
- Department of Clinical Pathology, El Ahrar Educational Hospital, Ministry of Health, Zagazig, Egypt
| | - Rehab M. Elgharabawy
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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28
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Li H, Yu J, Wu Y, Shao B, Wei X. In situ antitumor vaccination: Targeting the tumor microenvironment. J Cell Physiol 2020; 235:5490-5500. [PMID: 32030759 DOI: 10.1002/jcp.29551] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 01/07/2020] [Indexed: 02/05/2023]
Abstract
Tumor microenvironment is known to play important roles in tumor progression. Many therapies, targeting the tumor microenvironment, are designed and applied in the clinic. One of these approaches is in situ antitumor therapy. This way, bacteria, antibodies, plasmid DNA, viruses, and cells are intratumorally delivered into the tumor site as "in-situ antitumor vaccine," which seeks to enhance immunogenicity and generate systemic T cell responses. In addition, this intratumoral therapy can alter the tumor microenvironment from immunosuppressive to immunostimulatory while limiting the risk of systemic exposure and associated toxicity. Contemporarily, promising preclinical results and some initial success in clinical trials have been obtained after intratumoral therapy.
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Affiliation(s)
- Hanwen Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Jiayun Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Yongyao Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Bin Shao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
| | - Xiawei Wei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,State Key Laboratory of Biotherapy, Cancer Center, Sichuan University, Chengdu, China
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29
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Yamazaki T, Vanpouille-Box C, Demaria S, Galluzzi L. Immunogenic Cell Death Driven by Radiation-Impact on the Tumor Microenvironment. Cancer Treat Res 2020; 180:281-296. [PMID: 32215874 DOI: 10.1007/978-3-030-38862-1_10] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Immunogenic cell death (ICD) is a particular form of cell death that can initiate adaptive immunity against antigens expressed by dying cells in the absence of exogenous adjuvants. This implies that cells undergoing ICD not only express antigens that are not covered by thymic tolerance, but also deliver adjuvant-like signals that enable the recruitment and maturation of antigen-presenting cells toward an immunostimulatory phenotype, culminating with robust cross-priming of antigen-specific CD8+ T cells. Such damage-associated molecular patterns (DAMPs), which encompass cellular proteins, small metabolites and cytokines, are emitted in a spatiotemporally defined manner in the context of failing adaptation to stress. Radiation therapy (RT) is a bona fide inducer of ICD, at least when employed according to specific doses and fractionation schedules. Here, we discuss the mechanisms whereby DAMPs emitted by cancer cells undergoing RT-driven ICD alter the functional configuration of the tumor microenvironment.
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Affiliation(s)
- Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Claire Vanpouille-Box
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
- Université de Paris, Paris, France.
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30
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Hou J, Zhang H, Sun B, Karin M. The immunobiology of hepatocellular carcinoma in humans and mice: Basic concepts and therapeutic implications. J Hepatol 2020; 72:167-182. [PMID: 31449859 DOI: 10.1016/j.jhep.2019.08.014] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/02/2019] [Accepted: 08/14/2019] [Indexed: 02/08/2023]
Abstract
Basic and clinical studies have demonstrated the efficacy of immunotherapy, a technical and conceptual breakthrough that has revolutionised cancer treatment. Hepatocellular carcinoma (HCC), a deadly malignancy with aetiologic diversity and a chronic course, is strongly influenced by the immune system, and was recently found to partially benefit from immune-checkpoint inhibitor therapy. Notably, HCC onco-immunology depends on diverse genetic and environmental factors that together shape cancer-promoting inflammation and immune dysfunction - critical processes that control HCC malignant progression and response to therapy. Herein, we summarise the current understanding of liver and HCC onco-immunology obtained through basic studies with mouse models and clinical practice in humans. In particular, we discuss preclinical and clinical findings that implicate immunomodulation as a major factor in HCC development and explain the basis for HCC-targeting immunotherapy.
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Affiliation(s)
- Jiajie Hou
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Haiyan Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
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31
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Bianchi F, Milione M, Casalini P, Centonze G, Le Noci VM, Storti C, Alexiadis S, Truini M, Sozzi G, Pastorino U, Balsari A, Tagliabue E, Sfondrini L. Toll-like receptor 3 as a new marker to detect high risk early stage Non-Small-Cell Lung Cancer patients. Sci Rep 2019; 9:14288. [PMID: 31582772 PMCID: PMC6776648 DOI: 10.1038/s41598-019-50756-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 08/30/2019] [Indexed: 01/03/2023] Open
Abstract
Immune and epithelial cells express TLR3, a receptor deputed to respond to microbial signals activating the immune response. The prognostic value of TLR3 in cancer is debated and no data are currently available in NSCLC, for which therapeutic approaches that target the immune system are providing encouraging results. Dissecting the lung immune microenvironment could provide new prognostic markers, especially for early stage NSCLC for which surgery is the only treatment option. In this study we investigated the expression and the prognostic value of TLR3 on both tumor and immune compartments of stage I NSCLCs. In a cohort of 194 NSCLC stage I, TLR3 immunohistochemistry expression on tumor cells predicted a favorable outcome of early stage NSCLC, whereas on the immune cells infiltrating the tumor stroma, TLR3 expression associated with a poor overall survival. Patients with TLR3-positive immune infiltrating cells, but not tumor cells showed a worse prognosis compared with all other patients. The majority of TLR3-expressing immune cells resulted to be macrophages and TLR3 expression associates with PD-1 expression. TLR3 has an opposite prognostic significance when expressed on tumor or immune cells in early stage NCSCL. Analysis of TLR3 in tumor and immune cells can help in identifying high risk stage I patients for which adjuvant treatment would be beneficial.
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Affiliation(s)
- Francesca Bianchi
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Massimo Milione
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Patrizia Casalini
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Giovanni Centonze
- First Pathology Unit, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy.,Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Valentino M Le Noci
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy.,Università degli Studi di Milano, Dipartimento di Scienze Biomediche per la Salute, via Mangiagalli 31, 20133, Milan, Italy
| | - Chiara Storti
- Università degli Studi di Milano, Dipartimento di Scienze Biomediche per la Salute, via Mangiagalli 31, 20133, Milan, Italy
| | - Spyridon Alexiadis
- Pathological Anatomy Unit, ASST Grande Ospedale Metropolitano Niguarda, Piazza dell'Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Mauro Truini
- Pathological Anatomy Unit, ASST Grande Ospedale Metropolitano Niguarda, Piazza dell'Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Gabriella Sozzi
- Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Ugo Pastorino
- Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Andrea Balsari
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy. .,Università degli Studi di Milano, Dipartimento di Scienze Biomediche per la Salute, via Mangiagalli 31, 20133, Milan, Italy.
| | - Elda Tagliabue
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133, Milan, Italy
| | - Lucia Sfondrini
- Università degli Studi di Milano, Dipartimento di Scienze Biomediche per la Salute, via Mangiagalli 31, 20133, Milan, Italy
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Bonnin M, Fares N, Testoni B, Estornes Y, Weber K, Vanbervliet B, Lefrançois L, Garcia A, Kfoury A, Pez F, Coste I, Saintigny P, Viari A, Lang K, Guey B, Hervieu V, Bancel B, Bartoch B, Durantel D, Renno T, Merle P, Lebecque S. Toll-like receptor 3 downregulation is an escape mechanism from apoptosis during hepatocarcinogenesis. J Hepatol 2019; 71:763-772. [PMID: 31220470 DOI: 10.1016/j.jhep.2019.05.031] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/17/2019] [Accepted: 05/21/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Low levels of toll-like receptor 3 (TLR3) in patients with hepatocellular carcinoma (HCC) are associated with poor prognosis, primarily owing to the loss of inflammatory signaling and subsequent lack of immune cell recruitment to the liver. Herein, we explore the role of TLR3-triggered apoptosis in HCC cells. METHODS Quantitative reverse transcription PCR, western blotting, immunohistochemistry and comparative genomic hybridization were used to analyze human and mouse HCC cell lines, as well as surgically resected primary human HCCs, and to study the impact of TLR3 expression on patient outcomes. Functional analyses were performed in HCC cells, following the restoration of TLR3 by lentiviral transduction. The role of TLR3-triggered apoptosis in HCC was analyzed in vivo in a transgenic mouse model of HCC. RESULTS Lower expression of TLR3 in tumor compared to non-tumor matched tissue was observed at both mRNA and protein levels in primary HCC, and was predictive of shorter recurrence-free survival after surgical resection in both univariate (hazard ratio [HR] 1.79; 95% CI 1.04-3.06; p = 0.03) and multivariate analyses (HR 1.73; CI 1.01-2.97; p = 0.04). Immunohistochemistry confirmed frequent downregulation of TLR3 in human and mouse primary HCC cells. None of the 6 human HCC cell lines analyzed expressed TLR3, and ectopic expression of TLR3 following lentiviral transduction not only restored the inflammatory response but also sensitized cells to TLR3-triggered apoptosis. Lastly, in the transgenic mouse model of HCC, absence of TLR3 expression was accompanied by a lower rate of preneoplastic hepatocyte apoptosis and accelerated hepatocarcinogenesis without altering the tumor immune infiltrate. CONCLUSION Downregulation of TLR3 protects transforming hepatocytes from direct TLR3-triggered apoptosis, thereby contributing to hepatocarcinogenesis and poor patient outcome. LAY SUMMARY Hepatocellular carcinoma (HCC) is a heterogeneous disease associated with a poor prognosis. In patients with HCC, TLR3 downregulation is associated with reduced survival. Herein, we show that the absence of TLR3 is associated with a lower rate of apoptosis, and subsequently more rapid hepatocarcinogenesis, without any change to the immune infiltrate in the liver. Therefore, the poor prognosis associated with low TLR3 expression in HCC is likely linked to tumors ability to escape apoptosis. TLR3 may become a promising therapeutic target in TLR3-positive HCC.
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Affiliation(s)
- Marc Bonnin
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Nadim Fares
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Barbara Testoni
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Yann Estornes
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Kathrin Weber
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Béatrice Vanbervliet
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Lydie Lefrançois
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Amandine Garcia
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Alain Kfoury
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Floriane Pez
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Isabelle Coste
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Pierre Saintigny
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Department of Translational Research and Innovation and Department of Medicine, Centre Léon Bérard, Lyon, France
| | - Alain Viari
- Synergie Lyon Cancer, Plateforme de Bioinformatique 'Gilles Thomas' Centre Léon Bérard, Lyon, France
| | - Kévin Lang
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Baptiste Guey
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Valérie Hervieu
- Service d'Anatomopathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
| | - Brigitte Bancel
- Service d'Anatomopathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
| | - Birke Bartoch
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - David Durantel
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Toufic Renno
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Philippe Merle
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Groupement Hospitalier Lyon Nord, Hepatology Unit, Lyon, France.
| | - Serge Lebecque
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Hospices Civils de Lyon, Laboratoire d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
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33
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Juengpanich S, Shi L, Iranmanesh Y, Chen J, Cheng Z, Khoo AKJ, Pan L, Wang Y, Cai X. The role of natural killer cells in hepatocellular carcinoma development and treatment: A narrative review. Transl Oncol 2019; 12:1092-1107. [PMID: 31176993 PMCID: PMC6558093 DOI: 10.1016/j.tranon.2019.04.021] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 04/11/2019] [Accepted: 04/11/2019] [Indexed: 12/12/2022] Open
Abstract
A major obstacle for treatment of HCC is the inadequate efficacy and limitation of the available therapeutic options. Despite the recent advances in developing novel treatment options, HCC still remains one of the major causes of cancer morbidity and mortality around the world. Achieving effective treatment and eradication of HCC is a challenging task, however recent studies have shown that targeting Natural Killer cells, as major regulators of immune system, can help with the complete treatment of HCC, restoration of normal liver function and subsequently higher survival rate of HCC patients. Studies have shown that decrease in the frequency of NK cells, their dysfunction due to several factors such as dysregulation of receptors and their ligands, and imbalance of different types of inhibitory and stimulating microRNA expression is associated with higher rate of HCC progression and development, and poor survival outcome. Here in our review, we mainly focused on the importance of NK cells in HCC development and treatment.
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Affiliation(s)
- Sarun Juengpanich
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, Zhejiang, Province, China; School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Liang Shi
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, Zhejiang, Province, China.
| | | | - Jiang Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, Zhejiang, Province, China; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| | - Zhenzhe Cheng
- School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Aaron Kah-Jin Khoo
- Faculty of Medicine, The University of Queensland, St Lucia, QLD, 4027, Australia.
| | - Long Pan
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, Zhejiang, Province, China; School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Yifan Wang
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, Zhejiang, Province, China.
| | - Xiujun Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, Zhejiang, Province, China.
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Patra MC, Shah M, Choi S. Toll-like receptor-induced cytokines as immunotherapeutic targets in cancers and autoimmune diseases. Semin Cancer Biol 2019; 64:61-82. [PMID: 31054927 DOI: 10.1016/j.semcancer.2019.05.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 04/27/2019] [Accepted: 05/01/2019] [Indexed: 12/14/2022]
Abstract
Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling molecules that are structurally and functionally distinct from one another, although their secretion profiles and signaling cascades often overlap. This situation gives rise to pleiotropic cell-to-cell communication pathways essential for protection from infections as well as cancers. Nonetheless, deregulated signaling can have detrimental effects on the host, in the form of inflammatory or autoimmune diseases. Because cytokines are associated with numerous autoimmune and cancerous conditions, therapeutic strategies to modulate these molecules or their biological responses have been immensely beneficial over the years. There are still challenges in the regulation of cytokine function in patients, even in those who take approved biological therapeutics. In this review, our purpose is to discuss the differential expression patterns of TLR-regulated cytokines and their cell type specificity that is associated with cancers and immune-system-related diseases. In addition, we highlight key structural features and molecular recognition of cytokines by receptors; these data have facilitated the development and approval of several biologics for the treatment of autoimmune diseases and cancers.
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Affiliation(s)
- Mahesh Chandra Patra
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea
| | - Masaud Shah
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
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Chew V, Lee YH, Pan L, Nasir NJM, Lim CJ, Chua C, Lai L, Hazirah SN, Lim TKH, Goh BKP, Chung A, Lo RHG, Ng D, Filarca RLF, Albani S, Chow PKH. Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut 2019; 68:335-346. [PMID: 29440463 PMCID: PMC6352403 DOI: 10.1136/gutjnl-2017-315485] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/29/2017] [Accepted: 12/15/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response. DESIGN Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. RESULTS TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. CONCLUSION High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.
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Affiliation(s)
- Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Yun Hua Lee
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Lu Pan
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Nurul J M Nasir
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Chun Jye Lim
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Camillus Chua
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Liyun Lai
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Sharifah Nur Hazirah
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Tony Kiat Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore,Duke-NUS Medical School, Singapore
| | - Brian K P Goh
- Duke-NUS Medical School, Singapore,National Cancer Centre, Singapore,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Alexander Chung
- Duke-NUS Medical School, Singapore,National Cancer Centre, Singapore,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Richard H G Lo
- Duke-NUS Medical School, Singapore,National Cancer Centre, Singapore,Department of Diagnostic Radiology, Singapore General Hospital, Singapore
| | - David Ng
- Duke-NUS Medical School, Singapore,National Cancer Centre, Singapore,Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore
| | - Rene L F Filarca
- Duke-NUS Medical School, Singapore,National Cancer Centre, Singapore,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Salvatore Albani
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore.
| | - Pierce K H Chow
- Duke-NUS Medical School, Singapore,National Cancer Centre, Singapore,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
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Tan LSY, Wong B, Gangodu NR, Lee AZE, Kian Fong Liou A, Loh KS, Li H, Yann Lim M, Salazar AM, Lim CM. Enhancing the immune stimulatory effects of cetuximab therapy through TLR3 signalling in Epstein-Barr virus (EBV) positive nasopharyngeal carcinoma. Oncoimmunology 2018; 7:e1500109. [PMID: 30377565 DOI: 10.1080/2162402x.2018.1500109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/05/2018] [Accepted: 07/07/2018] [Indexed: 10/28/2022] Open
Abstract
Cetuximab immunotherapy targeting the epidermal growth factor receptor (EGFR) has been used to treat nasopharyngeal cancer (NPC) with some success. Therefore, combining an immune adjuvant to boost the immune microenvironment may improve its clinical efficacy. Herein, we investigate the immune-stimulatory effects of Poly-ICLC (a TLR3 agonist) in enhancing cetuximab-based immunotherapy and correlate these responses with FcɣRIIIa (V158F) or TLR3 single nucleotide polymorphisms (SNPs- L412F and C829T) expressed on immune effector cells. We observed high levels of TLR3 mRNA in NPC cells; and both TLR3 and EGFR expression were unaffected by Poly-ICLC treatment. Cetuximab plus Poly-ICLC significantly enhanced NK-mediated ADCC through up-regulation of CD107a and Granzyme B expression. This effect was independent of FcɣRIIIa-V158F and TLR3-L412F or TLR3-C829T polymorphisms expressed on NK cells. Additionally, IFN-ɣ expression and secretion were doubled following cetuximab plus poly-ICLC treatment; compared to either treatment alone. This effect was independent of TLR3 polymorphisms. Consequentially, adaptive immune responses were also seen with increased DC maturation (CD83), co-stimulatory molecules expression (CD80 and CD86) and increased frequency of EGFR-specific CD8 + T cells following Poly-ICLC treatment. The percentage of CD80+ CD83+ and CD83+ CD86+ DC was highest in the Poly-ICLC plus cetuximab group, compared to either treatment alone. These results demonstrate the effectiveness of Poly-ICLC in enhancing both cetuximab-mediated innate and adaptive anti-tumor immunity against NPC, which is independent of FcɣRIIIa-158, TLR3-L412F or TLR3-C829T polymorphisms. Additionally, Poly-ICLC does not downregulate EGFR expression on NPC cells and hence, will not dampen cetuximab anti-tumor activity.
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Affiliation(s)
- Louise Soo Yee Tan
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Benjamin Wong
- Department of Pathology, National University Health System Singapore, Singapore
| | - Nagaraja Rao Gangodu
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Andrea Zhe Ern Lee
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Anthony Kian Fong Liou
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Kwok Seng Loh
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore
| | - Hao Li
- Department of Otorhinolaryngology, Tan Tock Seng Hospital, Singapore
| | - Ming Yann Lim
- Department of Otorhinolaryngology, Tan Tock Seng Hospital, Singapore
| | | | - Chwee Ming Lim
- Department of Otolaryngology-Head and Neck Surgery, National University Health System Singapore, Singapore.,Department of Otolaryngology, National University of Singapore, Singapore
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Kyi C, Roudko V, Sabado R, Saenger Y, Loging W, Mandeli J, Thin TH, Lehrer D, Donovan M, Posner M, Misiukiewicz K, Greenbaum B, Salazar A, Friedlander P, Bhardwaj N. Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial. Clin Cancer Res 2018; 24:4937-4948. [PMID: 29950349 DOI: 10.1158/1078-0432.ccr-17-1866] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/12/2017] [Accepted: 06/21/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells.Patients and Methods: In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood.Results: Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (<grade 2). In the patient with clinical benefit, IHC analysis of tumor showed increased CD4, CD8, PD1, and PD-L1 levels compared with patients with progressive disease. RNA-seq analysis of the same patient's tumor and peripheral blood mononuclear cells showed dramatic changes in response to poly-ICLC treatment, including upregulation of genes associated with chemokine activity, T-cell activation, and antigen presentation.Conclusions: Poly-ICLC was well tolerated in patients with solid cancer and generated local and systemic immune responses, as evident in the patient achieving clinical benefit. These results warrant further investigation and are currently being explored in a multicenter phase II clinical trial (NCT02423863). Clin Cancer Res; 24(20); 4937-48. ©2018 AACR.
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Affiliation(s)
- Chrisann Kyi
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Vladimir Roudko
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Rachel Sabado
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - William Loging
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - John Mandeli
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tin Htwe Thin
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Deborah Lehrer
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Michael Donovan
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marshall Posner
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Benjamin Greenbaum
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Philip Friedlander
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nina Bhardwaj
- Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York.
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Bernsmeier C, Triantafyllou E, Brenig R, Lebosse FJ, Singanayagam A, Patel VC, Pop OT, Khamri W, Nathwani R, Tidswell R, Weston CJ, Adams DH, Thursz MR, Wendon JA, Antoniades CG. CD14 + CD15 - HLA-DR - myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure. Gut 2018; 67:1155-1167. [PMID: 28592438 PMCID: PMC5969362 DOI: 10.1136/gutjnl-2017-314184] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 04/26/2017] [Accepted: 04/27/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. DESIGN Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. RESULTS Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. CONCLUSION Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
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Affiliation(s)
- Christine Bernsmeier
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK,Liver Biology Laboratory, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Evangelos Triantafyllou
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK,Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK,Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Robert Brenig
- Liver Biology Laboratory, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Fanny J Lebosse
- Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK
| | - Arjuna Singanayagam
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK,Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK,Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Vishal C Patel
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK
| | - Oltin T Pop
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK
| | - Wafa Khamri
- Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK
| | - Rooshi Nathwani
- Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK
| | - Robert Tidswell
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK
| | - Christopher J Weston
- Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David H Adams
- Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Mark R Thursz
- Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK
| | - Julia A Wendon
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK
| | - Charalambos Gustav Antoniades
- Institute of Liver Studies, King’s College Hospital, King’s College London, London, UK,Division of Digestive Diseases, St. Mary’s Campus, Imperial College London, London, UK,Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK
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Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells. Oncotarget 2018; 8:32884-32904. [PMID: 28427199 PMCID: PMC5464836 DOI: 10.18632/oncotarget.15862] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/07/2017] [Indexed: 12/15/2022] Open
Abstract
Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyI:C, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyI:C reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyI:C suppressed the proliferation and survival of metastatic (NCI-H358 and NCI-H292) and non-metastatic (A549) lung cancer cells. Notably, A549, NCI-H292 and NCI-H358 which are inducible by polyI:C, expressed low-to-medium level of TLR3 protein, and were susceptible to polyI:C treatment. By contrast, NCI-H1299, which endogenously expresses high level of TLR3 protein, was insensitive to polyI:C. We showed that polyI:C stimulated pro-inflammatory cytokines associated with survival and metastasis in a cell type-specific manner. While A549 and NCI-H292 released high levels of IL6, IL8 and GRO, the NCI-H358 cells endogenously secretes abundant levels of these cytokines, and was not further induced by polyI:C. Thus, NCI-H358 was resistant to the inhibition of cytokine-dependent metastasis. NCI-H1299, which was unresponsive to polyI:C, did not produce any of the pro-inflammatory cytokines. Treatment of A549 with a combination of polyI:C and anti-IL6 antibody significantly decreased IL6 production, and enhanced polyI:C-mediated killing and suppression of oncogenicity and metastasis. While polyI:C stimulated the phosphorylation of STAT3 and JAK2, blockade of these proteins enhanced polyI:C-mediated suppression of survival and metastasis. Taken together, polyI:C alone provoked apoptosis of lung cancer cells that express low-to-medium levels of functional TLR3 protein. The combinatorial treatment with polyI:C and anti-IL6 enhanced polyI:C-mediated anticancer activities through IL6/JAK2/STAT3 signalling, and apoptosis via TLR3-mediated caspase 3/8 pathway.
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Feng Y, Chen Y, Meng Y, Cao Q, Liu Q, Ling C, Wang C. Bufalin Suppresses Migration and Invasion of Hepatocellular Carcinoma Cells Elicited by Poly (I:C) Therapy. Oncoimmunology 2018; 7:e1426434. [PMID: 29721392 PMCID: PMC5927531 DOI: 10.1080/2162402x.2018.1426434] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/05/2018] [Accepted: 01/07/2018] [Indexed: 02/06/2023] Open
Abstract
The Toll-like receptor 3 (TLR3) agonists as polyriboinosinic–polyribocytidylic acid (poly (I:C)) have been implicated as potential immunotherapy adjuvant for cancer whereas the exact roles of TLR3 agonists in hepatocellular carcinoma (HCC) treatment have not been clearly evaluated. In consistent with previous reports, we found that poly (I:C) triggering of TLR3 inhibited cell proliferation and induced apoptosis in HCC cells. However, poly (I:C), when used at lower concentration that cannot remarkably inhibit proliferation and induce apoptosis in HCC cells, enhanced the migration and invasion in vitro and the metastasis in vivo. More importantly, we found that bufalin, a prominent component of toad venom, could suppress poly (I:C)-inspired migration, invasion and metastasis of HCC cells despite that bufalin could not potentiate poly (I:C)-induced inhibition of proliferation and induction of apoptosis. In MHCC97 H cells, bufalin impaired poly (I:C)-induced activation of Tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway and NF-κB pathway. Inhibitor for TBK1 but not NF-κB suppressed poly (I:C)-inspired migration and invasion, which was further supported by using TBK1 deficient (Tbk1–/–) cells. In another model using poly (I:C) transfection, bufalin could also suppress the migration and invasion of HCC cells, which was not observed in Tbk1–/– MHCC97 H cells. Our data suggest that bufalin can suppress the metastasis of HCC cells in poly (I:C) therapy by impairing TBK1 activation, indicating that bufalin may be used in combination with poly (I:C) therapy in HCC treatment for the sake of reversing poly (I:C)-triggered metastasis of HCC cells.
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Affiliation(s)
- Yinglu Feng
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.,Department of Traditional Chinese Medicine, 401 Hospital of the Chinese People's Liberation Army, Qingdao, Shandong, China
| | - Yongan Chen
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yongbin Meng
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qingxin Cao
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qun Liu
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Changquan Ling
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chen Wang
- Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
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Sato Y, Motoyama S, Wakita A, Kawakita Y, Liu J, Nagaki Y, Nanjo H, Terata K, Imai K, Saito H, Minamiya Y. TLR3 expression status predicts prognosis in patients with advanced thoracic esophageal squamous cell carcinoma after esophagectomy. Am J Surg 2018; 216:319-325. [PMID: 29395019 DOI: 10.1016/j.amjsurg.2018.01.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 09/05/2017] [Accepted: 01/23/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND The relationship between Toll-like receptors (TLRs) and esophageal squamous cell carcinoma (ESCC) is not completely understood. METHODS RT-qPCR was used to evaluate the mRNA expression of TLR1-10 in 13 ESCC lines. We then used ESCC tissue microarray (TMA) to confirm expression of TLR3 protein in patients with ESCC. RESULTS All ESCC lines showed 10-60 times higher TLR3 mRNA expression than PBLs. High expression of TLR3 correlated with favorable 5-year overall survival (OS) and disease specific survival (DSS) among patients with ESCC after esophagectomy (p < 0.01). Additionally, In the adjuvant chemotherapy group, TLR3 high patients had significantly better 5-year OS compared to TLR3 low patients (60.2%, 34.4%, respectively) but not in the surgery alone group. CONCLUSION High TLR3 expression is an independent prognostic factor and has the potential to serve as a clinically useful marker of the need for adjuvant chemotherapy after esophagectomy in patients with advanced thoracic ESCC.
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Affiliation(s)
- Yusuke Sato
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
| | - Satoru Motoyama
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Akiyuki Wakita
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yuta Kawakita
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Jiajia Liu
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yushi Nagaki
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Hiroshi Nanjo
- Dept. of Pathology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Kaori Terata
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Kazuhiro Imai
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Hajime Saito
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yoshihiro Minamiya
- Dept. of Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Nguyen AT, Chia J, Ros M, Hui KM, Saltel F, Bard F. Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis. Cancer Cell 2017; 32:639-653.e6. [PMID: 29136507 DOI: 10.1016/j.ccell.2017.10.001] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 07/14/2017] [Accepted: 09/28/2017] [Indexed: 02/07/2023]
Abstract
Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.
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Affiliation(s)
- Anh Tuan Nguyen
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Joanne Chia
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Manon Ros
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Kam Man Hui
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Biochemistry, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore; Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore; Duke-NUS Graduate Medical School, Singapore, 8 College Road, Singapore 169857, Singapore
| | - Frederic Saltel
- INSERM, U1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000 Bordeaux, France; University of Bordeaux, U1053 Bordeaux Research In Translational Oncology, BaRITOn, 33000 Bordeaux, France
| | - Frederic Bard
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Biochemistry, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore.
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Hochnadel I, Kossatz-Boehlert U, Jedicke N, Lenzen H, Manns MP, Yevsa T. Cancer vaccines and immunotherapeutic approaches in hepatobiliary and pancreatic cancers. Hum Vaccin Immunother 2017; 13:2931-2952. [PMID: 29112462 PMCID: PMC5718787 DOI: 10.1080/21645515.2017.1359362] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary and pancreatic cancers along with other gastrointestinal malignancies remain the leading cause of cancer-related deaths worldwide. Strategies developed in the recent years on immunotherapy and cancer vaccines in the setting of primary liver cancer as well as in pancreatic cancer are the scope of this review. Significance of orthotopic and autochthonous animal models which mimic and/or closely reflect human malignancies allowing for a prompt and trustworthy analysis of new therapeutics is underlined. Combinational approaches that on one hand, specifically target a defined cancer-driving pathway, and on the other hand, restore the functions of immune cells, which effector functions are often suppressed by a tumor milieu, are shown to have the strongest perspectives and future directions. Among combinational immunotherapeutic approaches a personalized- and individual cancer case-based therapy is of special importance.
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Affiliation(s)
- Inga Hochnadel
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Uta Kossatz-Boehlert
- b Institute for Neuroanatomy, Eberhard-Karls University Tuebingen , Tuebingen , Germany
| | - Nils Jedicke
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Henrike Lenzen
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Michael P Manns
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Tetyana Yevsa
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
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Patidar A, Selvaraj S, Sarode A, Chauhan P, Chattopadhyay D, Saha B. DAMP-TLR-cytokine axis dictates the fate of tumor. Cytokine 2017; 104:114-123. [PMID: 29032985 DOI: 10.1016/j.cyto.2017.10.004] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/29/2017] [Accepted: 10/02/2017] [Indexed: 12/31/2022]
Abstract
Random mutations leading to loss of cell cycle control is not a rare occurrence in an organism but the mutated cells are recognized and eliminated preventing the development of a tumor. These potentially tumorigenic cells release damage-associated molecular patterns (DAMPs), which are recognized by toll-like receptors (TLRs) on macrophages and dendritic cells. The initial TLR-DAMP interactions lead to different responses such as altered antigen presentation and cytokine release that directly affect T cell activation and removal of the tumorigenic cells. The indirect effects of TLR-DAMP interaction include chemokine-directed altered T cell trafficking, angiogenesis for both T cell infiltration and tumor cell metastasis, and alteration of intra-tumoral milieu contributing to the development of tumor cells heterogeneity. Thus, the initial TLR-DAMP interaction has a set of local effects that modulate tumor cell growth and heterogeneity and a disseminating set of central effects that dynamically affect T cell trafficking and functions. Herein, we argue that the DAMP-TLR-cytokine axis in the tumor microenvironment serves as the mainstay that orchestrates and regulates the pro- and anti-tumor elements which dynamically interact between themselves eventuating in tumor regression or growth. The knowledge of this TLR-based immuno-surveillance framework is a key to developing a novel immunotherapy against cancer.
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Affiliation(s)
- Ashok Patidar
- National Centre for Cell Science, Ganeshkhind, Pune, India
| | | | - Aditya Sarode
- National Centre for Cell Science, Ganeshkhind, Pune, India
| | | | | | - Bhaskar Saha
- National Institute of Traditional Medicine, Belagavi, Karnataka, India.
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Bianchi F, Pretto S, Tagliabue E, Balsari A, Sfondrini L. Exploiting poly(I:C) to induce cancer cell apoptosis. Cancer Biol Ther 2017; 18:747-756. [PMID: 28881163 PMCID: PMC5678690 DOI: 10.1080/15384047.2017.1373220] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
TLR3 belong to the Toll-like receptors family, it is mainly expressed on immune cells where it senses pathogen-associated molecular patterns and initiates innate immune response. TLR3 agonist poly(I:C) was developed to mimic pathogens infection and boost immune system activation to promote anti-cancer therapy. Accordingly, TLR agonists were included in the National Cancer Institute list of immunotherapeutic agents with the highest potential to cure cancer. Besides well known effects on immune cells, poly(I:C) was also shown, in experimental models, to directly induce apoptosis in cancer cells expressing TLR3. This review presents the current knowledge on the mechanism of poly(I:C)-induced apoptosis in cancer cells. Experimental evidences on positive or negative regulators of TLR3-mediated apoptosis induced by poly(I:C) are reported and strategies are proposed to successfully promote this event in cancer cells. Cancer cells apoptosis is an additional arm offered by poly(I:C), besides activation of immune system, for the treatment of various type of cancer. A further dissection of TLR3 signaling would contribute to greater resolution of the critical steps that impede full exploitation of the poly(I:C)-induced apoptosis. Experimental evidences about negative regulator of poly(I:C)-induced apoptotic program should be considered in combinations with TLR3 agonists in clinical trials.
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Affiliation(s)
- Francesca Bianchi
- a Fondazione IRCCS Istituto Nazionale dei Tumori , Department of Research, Epidemiologia e Medicina Molecolare , via Amadeo 42, Milan , Italy.,b Università degli Studi di Milano , Dipartimento di Scienze Biomediche per la Salute , via Mangiagalli 31, Milan , Italy
| | - Samantha Pretto
- b Università degli Studi di Milano , Dipartimento di Scienze Biomediche per la Salute , via Mangiagalli 31, Milan , Italy
| | - Elda Tagliabue
- a Fondazione IRCCS Istituto Nazionale dei Tumori , Department of Research, Epidemiologia e Medicina Molecolare , via Amadeo 42, Milan , Italy
| | - Andrea Balsari
- a Fondazione IRCCS Istituto Nazionale dei Tumori , Department of Research, Epidemiologia e Medicina Molecolare , via Amadeo 42, Milan , Italy.,b Università degli Studi di Milano , Dipartimento di Scienze Biomediche per la Salute , via Mangiagalli 31, Milan , Italy
| | - Lucia Sfondrini
- b Università degli Studi di Milano , Dipartimento di Scienze Biomediche per la Salute , via Mangiagalli 31, Milan , Italy
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The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion. Nat Commun 2017; 8:15129. [PMID: 28541302 PMCID: PMC5529670 DOI: 10.1038/ncomms15129] [Citation(s) in RCA: 271] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 03/01/2017] [Indexed: 12/12/2022] Open
Abstract
Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma (HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC. The role of long noncoding RNAs in regulating T-cell differentiation within the tumour microenvironment is unclear. Here the authors identify a lncRNA that, through direct interactions with EGFR, promotes T-regulatory cell differentiation within the microenvironment of hepatocellular carcinoma, thus promoting tumour growth via immune suppression.
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Gene polymorphisms of TLR2 and TLR3 in HBV clearance and HBV-related hepatocellular carcinoma in a Chinese male population. Int J Biol Markers 2017; 32:e195-e201. [PMID: 28009434 DOI: 10.5301/jbm.5000238] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND The Toll-like receptor plays an essential role in controlling immunity and inflammation. This study was to investigate the relationships of genetic variants in TLR2 and TLR3 with hepatitis B virus (HBV) natural clearance and HBV-related hepatocellular carcinoma (HCC) risk in a Chinese male population. METHODS We analyzed 5 polymorphisms of TLR2 (rs3804099 and rs3804100) and TLR3 (rs5743305, rs3775296 and rs3775291) in a population consisting of 686 participants with HBV natural clearance, 293 chronic HBV carriers and 395 HBV-positive HCC patients, using the improved multiplex ligase detection reaction method. RESULTS After adjustment for age and smoking and drinking status, no associations were observed either between the 5 single-nucleotide polymorphisms (SNPs) and the HBV natural clearance participants, or between the 5 SNPs and HCC patients. Whereas the stratified analysis showed that under the dominant models, nondrinkers with TLR2 rs3804100 and participants younger than 40 years old with TLR3 rs3775291 were significantly associated with HCC risk when compared with persistent HBV carriers (adjusted odd ratio [OR] = 0.49, 95% confidence interval [95% CI], 0.31-0.78, p = 0.003; and adjusted OR = 0.50, 95% CI, 0.29-0.86, p = 0.013, respectively). Furthermore, the TTTCT haplotype was found to promote the progress of HBV clearance and inhibit development of HBV-related HCC (OR = 0.77, 95% CI, 0.61-0.97, p = 0.029; and OR = 0.72, 95% CI, 0.55-0.94, p = 0.016, respectively). And the CCACC and CCTCT haplotypes were observed to decrease susceptibility to HCC (OR = 0.64, 95% CI, 0.40-1.00, p = 0.048; and OR = 0.43, 95% CI, 0.28-0.68, p<0.001, respectively). CONCLUSIONS This study revealed that TLR2 rs3804100 and TLR3 rs3775291 polymorphisms may be protective factors for HBV-related HCC.
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Debes JD, Janssen HLA, Boonstra A. Hepatitis C treatment and liver cancer recurrence: cause for concern? Lancet Gastroenterol Hepatol 2017; 2:78-80. [DOI: 10.1016/s2468-1253(16)30204-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Revised: 11/24/2016] [Accepted: 11/26/2016] [Indexed: 12/15/2022]
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Ho V, Lim TS, Lee J, Steinberg J, Szmyd R, Tham M, Yaligar J, Kaldis P, Abastado JP, Chew V. TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression. Oncotarget 2016; 6:27252-66. [PMID: 26287667 PMCID: PMC4694987 DOI: 10.18632/oncotarget.4583] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/13/2015] [Indexed: 01/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8+ T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies.
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Affiliation(s)
- Victor Ho
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
| | - Tong Seng Lim
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
| | - Justin Lee
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
| | - Jeffrey Steinberg
- Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
| | - Radoslaw Szmyd
- Institute Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.,Department of Biochemistry, National University of Singapore (NUS), Singapore
| | - Muly Tham
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
| | - Jadegoud Yaligar
- Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
| | - Philipp Kaldis
- Institute Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.,Department of Biochemistry, National University of Singapore (NUS), Singapore
| | - Jean-Pierre Abastado
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.,Institut de Recherches Internationales Servier, Suresnes, France
| | - Valerie Chew
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.,Singhealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd., Singapore
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Dajon M, Iribarren K, Cremer I. Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword. Immunobiology 2016; 222:89-100. [PMID: 27349597 DOI: 10.1016/j.imbio.2016.06.009] [Citation(s) in RCA: 154] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 06/06/2016] [Accepted: 06/10/2016] [Indexed: 02/09/2023]
Abstract
Toll-like receptors (TLRs) are a family of transmembrane receptors that recognize various pathogen- and damage-associated molecular pattern molecules playing an important role in inflammation by activating NF-кB. TLRs, mainly expressed by innate immune cells, are involved in inducing and regulating adaptive immune responses. However, the expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. Here we review the role of TLRs in conferring anti- or pro-tumoral effects. The anti-tumoral effects can result from direct induction of tumor cell death and/or activation of efficient anti-tumoral immune responses, and the pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment.
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Affiliation(s)
- Marion Dajon
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris F-75006, France; Université Pierre et Marie Curie-Paris 6, UMRS1138, Paris F-75006, France; Université Paris Descartes, UMRS1138, Paris F-75006, France
| | - Kristina Iribarren
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris F-75006, France; Université Pierre et Marie Curie-Paris 6, UMRS1138, Paris F-75006, France; Université Paris Descartes, UMRS1138, Paris F-75006, France
| | - Isabelle Cremer
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris F-75006, France; Université Pierre et Marie Curie-Paris 6, UMRS1138, Paris F-75006, France; Université Paris Descartes, UMRS1138, Paris F-75006, France.
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