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Dong D, Yu X, Liu H, Xu J, Guo J, Guo W, Li X, Wang F, Zhang D, Liu K, Sun Y. Study of immunosenescence in the occurrence and immunotherapy of gastrointestinal malignancies. Semin Cancer Biol 2025; 111:16-35. [PMID: 39929408 DOI: 10.1016/j.semcancer.2025.01.007] [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: 12/15/2024] [Revised: 01/18/2025] [Accepted: 01/26/2025] [Indexed: 02/25/2025]
Abstract
In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.
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Affiliation(s)
- Daosong Dong
- Department of Pain, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xue Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in the Universities of Liaoning Province, Shenyang, Liaoning 110001, China
| | - Haoran Liu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jingjing Xu
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jiayan Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Fei Wang
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Dongyong Zhang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Kaiwei Liu
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Yanbin Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
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Huang Y, Wang D, Liu Y, Xu X, Chen L, Ma Z, Liu Z. Current research status and hotspots of precancerous lesions of gastric cancer: a bibliometric analysis. Front Oncol 2025; 15:1571617. [PMID: 40365340 PMCID: PMC12069070 DOI: 10.3389/fonc.2025.1571617] [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: 02/05/2025] [Accepted: 03/31/2025] [Indexed: 05/15/2025] Open
Abstract
Background Gastric cancer is the fifth most common cancer worldwide, and its lack of specific symptoms presents a significant challenge for early diagnosis. Therefore, the identification and detection of precancerous lesions of gastric cancer (PLGC) are essential for its prevention. We performed a comprehensive bibliometric analysis to explore the research trends and emerging topics in this field, aiming to deepen our understanding of PLGC. Objective This study utilizes a bibliometric approach with network analysis to explore the progress and trends in PLGC research. The findings aim to provide a foundation and guidance for further in-depth investigations into PLGC. Methods This study used VOSviewer and CiteSpace software to collect relevant literature on PLGC from the Web of Science Core Collection, covering the period from 2005 to 2024. Data visualization analysis was performed on the number of publications, countries, institutions, journals, authors, keywords, and citation counts of these articles. Results A total of 1,141 relevant articles were included in the analysis. The results showed a year-on-year increase in the number of publications from 2005 to 2024. The country, institution, author, and journal with the highest publication output in this field were China, Peking University, Wei-Cheng You, and World Journal of Gastroenterology, respectively. The most frequently occurring keywords in the PLGC field were "Helicobacter pylori," "intestinal metaplasia," "risk," "infection," and "atrophic gastritis." Additionally, "chronic atrophic gastritis" and "inflammation" have emerged as hot topics for future research. Conclusion This bibliometric analysis highlights the hot topics and emerging trends in PLGC research, aiming to provide valuable guidance for future studies. Our findings indicate that mechanistic studies and clinical diagnosis will be key areas of focus in upcoming research.
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Affiliation(s)
- Yan Huang
- First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Dexin Wang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Institute of Liver Diseases, Cell Biology Laboratory, Shanghai University of TCM, Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Clinical Key Laboratory of TCM of Shanghai, Shanghai, China
| | - Yuzhuo Liu
- Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Xiaonan Xu
- First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Li Chen
- Neonatology Department, Qiqihar Traditional Chinese Medicine Hospital, Qiqihar, China
| | - Zhuolin Ma
- Heilongjiang Eye Hospital, Harbin, China
| | - Zhaoxia Liu
- First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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Garre E, Rhost S, Gustafsson A, Szeponik L, Araujo TF, Quiding-Järbrink M, Helou K, Ståhlberg A, Landberg G. Breast cancer patient-derived scaffolds enhance the understanding of PD-L1 regulation and T cell cytotoxicity. Commun Biol 2025; 8:621. [PMID: 40240529 PMCID: PMC12003762 DOI: 10.1038/s42003-025-08054-3] [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: 01/08/2025] [Accepted: 04/08/2025] [Indexed: 04/18/2025] Open
Abstract
Recent advances as well as obstacles for immune-based cancer treatment strategies, highlight the notable impact of patient cancer microenvironments on the immune cells and immune targets. Here, we use patient-derived scaffolds (PDS) generated from 110 primary breast cancers to monitor the impact of the cancer microenvironment on immune regulators. Pronounced variation in PD-L1 expression is observed in cancer cells adapted to different patient scaffolds. This variation is further linked to clinical observations and correlated with specific proteins detected in the cell-free PDSs using mass spectrometry. When adding T cells to the PDS-based cancer cultures, the killing efficiency of activated T cells vary between the cultures, whereas non-activated T cells modulate the cancer cell PD-L1 expression to treatment-predictive values, matching killing capacities of activated T cells. Surviving cancer cells show enrichment in cancer stem cell and epithelial-to-mesenchymal transition (EMT) features, suggesting that T cells may not efficiently target cells with metastatic potential. We conclude that clinically relevant insights in how to optimally target and guide immune-based cancer therapies can be obtained by including patient-derived scaffolds and cues from the cancer microenvironment in cancer patient handling and drug development.
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Affiliation(s)
- Elena Garre
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
| | - Sara Rhost
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
| | - Anna Gustafsson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
| | - Louis Szeponik
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Thais Fenz Araujo
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
| | - Marianne Quiding-Järbrink
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Khalil Helou
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Ståhlberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Göran Landberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Xue X, Gajic ZZ, Caragine CM, Legut M, Walker C, Kim JYS, Wang X, Yan RE, Wessels HH, Lu C, Bapodra N, Gürsoy G, Sanjana NE. Paired CRISPR screens to map gene regulation in cis and trans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.27.625752. [PMID: 39651170 PMCID: PMC11623649 DOI: 10.1101/2024.11.27.625752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of either cis -regulatory elements (CREs) or trans -acting factors. Here, we develop a scalable approach that pairs cis - and trans -regulatory CRISPR screens to systematically dissect how the key immune checkpoint PD-L1 is regulated. In human pancreatic ductal adenocarcinoma (PDAC) cells, we tile the PD-L1 locus using ∼25,000 CRISPR perturbations in constitutive and IFNγ-stimulated conditions. We discover 67 enhancer- or repressor-like CREs and show that distal CREs tend to contact the promoter of PD-L1 and related genes. Next, we measure how loss of all ∼2,000 transcription factors (TFs) in the human genome impacts PD-L1 expression and, using this, we link specific TFs to individual CREs and reveal novel PD-L1 regulatory circuits. For one of these regulatory circuits, we confirm the binding of predicted trans -factors (SRF and BPTF) using CUT&RUN and show that loss of either the CRE or TFs potentiates the anti-cancer activity of primary T cells engineered with a chimeric antigen receptor. Finally, we show that expression of these TFs correlates with PD-L1 expression in vivo in primary PDAC tumors and that somatic mutations in TFs can alter response and overall survival in immune checkpoint blockade-treated patients. Taken together, our approach establishes a generalizable toolkit for decoding the regulatory landscape of any gene or locus in the human genome, yielding insights into gene regulation and clinical impact.
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Zhou Y, Luo Z, Guo J, Wu L, Zhou X, Huang JJ, Huang D, Xiao L, Duan Q, Chang J, Gong L, Hang J. Pan-cancer analysis of Sp1 with a focus on immunomodulatory roles in gastric cancer. Cancer Cell Int 2024; 24:338. [PMID: 39402565 PMCID: PMC11476248 DOI: 10.1186/s12935-024-03521-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Sp1, a transcription factor, regulates essential cellular processes and plays important tumorigenic roles across diverse cancers. However, comprehensive pan-cancer analyses of its expression and potential immunomodulatory roles remain unexplored. METHODS Utilizing bioinformatics tools and public datasets, we examined the expression of Sp1 across normal tissues, tumors, and immune cells, and screened for pre- and post-transcriptional modifications, including genetic alterations, DNA methylation, and protein phosphorylation, affecting its expression or function. The association of Sp1 expression with immune cell infiltration, tumor mutational burden, and immune checkpoint signaling was also investigated. Single-cell transcriptome data was used to assess Sp1 expression in immune cells in gastric cancer (GC), and findings were corroborated using immunohistochemistry and multiplex immunofluorescence in an immunotherapy-treated patient cohort. The prognostic value of Sp1 in GC patients receiving immunotherapy was evaluated with Cox regression models. RESULTS Elevated Sp1 levels were observed in various cancers compared to normal tissues, with notable prominence in GC. High Sp1 expression correlated with advanced stage, poor prognosis, elevated tumor mutational burden (TMB), and microsatellite instability (MSI) status, particularly in GC. Significant correlations between Sp1 levels and CD8+ T cell and the M1 phenotype of tumor-associated macrophages were further detected upon multiplex immunofluorescence in GC samples. Interestingly, we verified that GC patients with higher Sp1 levels exhibited improved response to immunotherapy. Moreover, Sp1 emerged as a prognostic and predictive biomarker for GC patients undergoing immunotherapy. CONCLUSIONS Our pan-cancer analysis sheds light on the multifaceted role of Sp1 in tumorigenesis and underscores its potential as a prognostic and predictive biomarker for patients with GC undergoing immunotherapy.
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Affiliation(s)
- Yang Zhou
- The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, 213000, China
| | - Zhenzhen Luo
- Department of Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China
| | - Jinfeng Guo
- Department of Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China
| | - Lixia Wu
- Department of Oncology, Shanghai JingAn District ZhaBei Central Hospital, Shanghai, 200070, China
| | - Xiaoli Zhou
- The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, 213000, China
| | - Jun Jie Huang
- JC School of Public Health and Primary Care, Faculty of Medicine, Centre for Health Education and Health Promotion, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Daijia Huang
- Department of Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China
| | - Li Xiao
- Department of Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China
| | - Qiuhua Duan
- The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, 213000, China
| | - Jianhua Chang
- Department of Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China.
| | - Libao Gong
- Department of Oncology, The Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, 519000, China.
| | - Junjie Hang
- Department of Oncology, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Shenzhen, 518116, China.
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Tsai CL, Tang YH, Yang LY, Chao A, Wang CJ, Lin CY, Lai CH. Inhibition of nucleophosmin/B23 sensitizes ovarian cancer cells to immune check-point blockade via PD-L1 in ovarian cancer. J Formos Med Assoc 2024; 123:1045-1056. [PMID: 38821736 DOI: 10.1016/j.jfma.2024.05.020] [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: 05/15/2023] [Revised: 03/05/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) that against programmed cell death protein-1 (PD-1) and its ligand PD-L1 have been approved as a promising treatment of many human cancers. However, the responses to these ICIs were limited in patients with ovarian cancer. Studies have indicated that the response to PD-1/PD-L1 blockade might be correlated with the PD-L1 expression level in cancer cells. Nucleophosmin (NPM/B23) was found to be a potential target for immunotherapy. Whether NPM/B23 plays a role in cancer-associated immunity, such as PD-1/PD-L1 axis, and its underlying mechanisms remain largely unknown in ovarian cancer. METHODS We applied ovarian cancer cell lines as research models. The effect of modulating PD-L1 by NPM/B23 was subsequently confirmed via Western blot, flow cytometry, qRT-PCR, luciferase reporter assays, and immunoprecipitation. Protein stability and ubiquitin assay assays were used to analyze the interplay between NPM/B23 and NF-ĸB/p65 in PD-L1 regulation. The MOSEC/Luc xenograft mouse model was used to validate the role of NPM/B23-PD-L1 through tumor growth in vivo. RESULTS Our results revealed that NPM/B23 negatively regulates PD-L1 expression via a protein complex with NF-κB/p65 and through an IFN-γ pathway. Moreover, NPM/B23 inhibitor/modulator sensitized ovarian cancer cells to the anti-PD-1 antibody by regulating PD-L1 expression in the immunocompetent mouse model. Compared to anti-PD-1 antibody alone, a combination of anti-PD-1 antibody and NPM/B23 inhibitor/modulator showed reduced tumorigenesis and increased CD8+ T-cell expansion, thus contributing to prolonged survival on MOSEC/Luc-bearing mouse model. CONCLUSION Targeting NPM/B23 is a novel and potential therapeutic approach to sensitize ovarian cancer cells to immunotherapy.
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Affiliation(s)
- Chia-Lung Tsai
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Yun-Hsin Tang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch, and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Lan-Yan Yang
- Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan; Biostatics Unit, and Clinical Trial Center, Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Taoyuan, Taiwan; Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Angel Chao
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch, and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chin-Jung Wang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch, and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chiao-Yun Lin
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch, and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan.
| | - Chyong-Huey Lai
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch, and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan.
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Yang M, Liu Y, Zheng S, Geng P, He T, Lu L, Feng Y, Jiang Q. Associations of PD-1 and PD-L1 gene polymorphisms with cancer risk: a meta-analysis based on 50 studies. Aging (Albany NY) 2024; 16:6068-6097. [PMID: 38546391 PMCID: PMC11042937 DOI: 10.18632/aging.205689] [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: 04/03/2023] [Accepted: 02/27/2024] [Indexed: 04/23/2024]
Abstract
Programmed death-1 and its ligand-1 (PD-1/PD-L1), immune checkpoints proteins, play a crucial role in anti-tumor responses. A large number of studies have evaluated the relationships of PD-1/PD-L1 polymorphisms with risk of cancer, but evidence for the associations remains inconsistent. Therefore, we performed a meta-analysis to examine the associations between PD-1/PD-L1 single nucleotide polymorphisms (SNPs) and cancer predisposition. Results showed that PD-1.3 and PD-L1 rs17718883 were significantly correlated with overall cancer risk. PD-1.5 was prominently linked with cervical cancer (CC), non-small cell lung cancer (NSCLC), TC (thyroid cancer), brain tumor, AML (acute myelocytic leukemia) and UCC (urothelial cell carcinoma) risk, PD-1.9 with breast cancer (BC), AML, esophageal cancer (EC) and ovarian cancer (OC) risk, and PD-1.3 with colorectal cancer (CRC) and BCC (basal cell carcinoma) risk. PD-1.1 polymorphism slightly elevated BC and OC susceptibility, whereas the rs4143815 variant notably decreased the risk of gastric cancer (GC), hepatocellular carcinoma (HCC) and OC, but increased the risk of BC. PD-1.6 was closely linked with AML risk, PD-L1 rs2890658 with NSCLC, HCC and BC risk, rs17718883 with HCC and GC risk, rs10815225 with GC risk, and rs2297136 with NSCLC and HCC risk. Interestingly, the rs7421861, rs10815225, and rs10815225 markedly reduced cancer susceptibility among Asians. The rs7421861 polymrophism decreased cancer risk among Caucasians, rather than the rs10815225 elevated cancer risk. Our results supported that PD-1 and PD-L1 SNPs were dramatically correlated with cancer risk.
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Affiliation(s)
- Maoquan Yang
- School of Clinical Medicine, Shandong Second Medical University, Weifang 261042, Shandong, China
| | - Yan Liu
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Shandong Second Medical University, Kuiwen, Weifang 261000, Shandong, China
| | - Shuangshuang Zheng
- Department of Health, Weifang People’s Hospital, The First Affiliated Hospital of Shandong Second Medical University, Kuiwen, Weifang 261000, Shandong, China
| | - Peizhen Geng
- School of Clinical Medicine, Shandong Second Medical University, Weifang 261042, Shandong, China
| | - Tianhao He
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Shandong Second Medical University, Kuiwen, Weifang 261000, Shandong, China
| | - Linan Lu
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Shandong Second Medical University, Kuiwen, Weifang 261000, Shandong, China
| | - Yikuan Feng
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Shandong Second Medical University, Kuiwen, Weifang 261000, Shandong, China
| | - Qiqi Jiang
- Department of Gastroenterology, Weifang People’s Hospital, The First Affiliated Hospital of Shandong Second Medical University, Kuiwen, Weifang 261000, Shandong, China
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Hlaing STM, Damayanti P, Zin Aung K, Tsukino H, Hinoura T, Kuroda Y. The Relationship Between PD-1(rs2227981) and PD-L1(rs2890658) Polymorphisms and Urothelial Cell Carcinoma. Cureus 2023; 15:e48120. [PMID: 38046711 PMCID: PMC10693471 DOI: 10.7759/cureus.48120] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2023] [Indexed: 12/05/2023] Open
Abstract
Background Urothelial cell carcinoma, which is believed to develop from the urothelium (transitional epithelium), is the most common aggressive tumor and accounts for the ten most prevalent cancers in the world. The risk factors for urothelial cell carcinoma are aging, smoking, gender, and genetic alternations. Programmed cell death1 (PD-1) has been widely described as a negative regulator of T-cells by sending inhibitory signals to the T-cell. Through PD-1 binding with PD-L1 (ligand for PD-1), an inhibitory signal is propagated to the T cell. The polymorphisms of PD-1 and PD-L1 lead to an efficient T-cell response and affect an anti-tumor reaction. The polymorphisms of PD-1 and PD-L1 could also affect the carcinogenesis of human cancer, including urothelial cell carcinoma. Therefore, in this study, we evaluated the relation between PD-1(rs2227981) and PD-L1(rs2890658) polymorphisms and the carcinogenesis of urothelial cell carcinoma. Materials and methods This study was conducted using 211 healthy controls and 256 cases of urothelial cell carcinoma among the Japanese population. The DNA samples were extracted from the peripheral white blood cells of each subject. The genotype was detected by using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Results C/T (Adjusted OR 1.55, 95% CI:1.02-2.35) and C/T+T/T (OR 1.46, 95% CI:1.01-2.12) genotypes of PD-1 rs2227981 were significant and risk factors for urothelial cancer. Male with A/A genotype in PD-L1 and CT genotype in PD-1 has a significant higher risk factor compared with other genotypes (Adjusted OR 1.83, 95% CI:1.05-3.21). Conclusions and discussion We found that C/T(PD-1) and "A/A (PD-L1) and C/T(PD-1)" were predominant in urothelial cell carcinoma cases. This indicates that C/T(PD-1) and "A/A (PD-L1) and C/T(PD-1)" genotypes could increase susceptibility to urothelial cell carcinoma. However, since our findings indicated that the effects of PD-1 and PD-L1 polymorphisms included discrepancies, additional research will be needed to evaluate the relationship between human cancer and PD-1 and PD-L1 polymorphisms. This is the first study that seeks to find the relation between PD-1(rs2227981) and PD-L1(rs2890658) polymorphisms concerning urothelial cell carcinoma among the Japanese population.
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Affiliation(s)
- Sa Tin Myo Hlaing
- Department of Public Health, Faculty of Medicine, University of Miyazaki, Miyazaki, JPN
| | - Putri Damayanti
- Department of Public Health, Faculty of Medicine, University of Miyazaki, Miyazaki, JPN
| | - Khine Zin Aung
- Department of Public Health, Faculty of Medicine, University of Miyazaki, Miyazaki, JPN
| | - Hiromasa Tsukino
- Department of Urology, Junwakai Memorial Hospital, Miyazaki, JPN
| | - Takuji Hinoura
- Department of Public Health, Faculty of Medicine, University of Miyazaki, Miyazaki, JPN
| | - Yoshiki Kuroda
- Department of Public Health, Faculty of Medicine, University of Miyazaki, Miyazaki, JPN
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Yang J, Meng L, Yang Y, Gao H, Jiang H. Elevated programmed cell death-1 protein/ligand (PD-1/PD-L1) and variants are associated with susceptibility to multiple myeloma: a case-control study in the Chinese cohort. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:230-248. [PMID: 37688463 DOI: 10.1080/15257770.2023.2253276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/14/2023] [Accepted: 08/24/2023] [Indexed: 09/11/2023]
Abstract
Multiple myeloma (MM) is a malignant disorder characterised by progressive immune dysregulation. The importance of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) in MM has been documented in various populations, but studies have been limited to the Chinese cohort. In the present study, we examined the role of PD-1/PDL-1 in large cohorts of Chinese patients with MM and healthy controls to reveal a possible association with MM. Three hundred thirty-four MM patients and 202 healthy age-sex-matched subjects were enrolled in the present study. Serum levels of PD-1 and PD-L1 were quantified by ELISA. Percentages of T cells (CD4+ and CD8+ T cells) expressing PD-1 receptor were assessed by flow cytometry. Variants in PD-L1 (rs4143815) and PD-1 gene (rs2227981, rs2227982, rs7421861 and rs11568821) were genotyped by PCR-RFLP method. Patients with multiple myeloma had higher levels of PD-1 and PDL-1 than healthy controls, indicating an important role for programmed cell death protein-1 and its ligand in the pathogenesis of MM. T cells expressing PD-1 receptors were also significantly higher in MM patients than in controls. Mutants for PD-L1 (rs4143815) and PD-1 (rs2227982 and rs7421861) polymorphisms were significantly more common in MM than in HC. Interestingly, PD-L1 (rs4143815) and PD-1 (rs2227982 and rs7421861) variants were linked to higher sPD-L1 and sPD-1 levels, respectively. PD-1/PD-L1 levels are significantly higher in MM patients and could be a promising biomarker for the disease. Variants of PD-L1 and PD-1 are linked to serum-soluble proteins and are associated with the development of MM.
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Affiliation(s)
- Jing Yang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Ling Meng
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yongxin Yang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hongwei Gao
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Honggang Jiang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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10
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Xin Z, You L, Li J, Na F, Chen M, Song J, Bai L, Chen H, Zhai J, Zhou X, Zhou J, Ying B. Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade. Int Immunopharmacol 2023; 121:110469. [PMID: 37311357 DOI: 10.1016/j.intimp.2023.110469] [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: 05/08/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. METHODS Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. RESULTS Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. CONCLUSION Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.
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Affiliation(s)
- Zhaodan Xin
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Liting You
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China; Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Jin Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Feifei Na
- Department of Thoracic Cancer, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Min Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province 570102, PR China
| | - Jiajia Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Ling Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Hao Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Jianzhao Zhai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Xiaohan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China.
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China.
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11
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PD-L1: expression regulation. BLOOD SCIENCE 2023; 5:77-91. [DOI: 10.1097/bs9.0000000000000149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/29/2022] [Indexed: 02/05/2023] Open
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12
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Li Y, Yoon B, Dey A, Nguyen VQ, Park JH. Recent progress in nitric oxide-generating nanomedicine for cancer therapy. J Control Release 2022; 352:179-198. [PMID: 36228954 DOI: 10.1016/j.jconrel.2022.10.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/26/2022] [Accepted: 10/05/2022] [Indexed: 11/06/2022]
Abstract
Nitric oxide (NO) is an endogenous, multipotent biological signaling molecule that participates in several physiological processes. Recently, exogenous supplementation of tumor tissues with NO has emerged as a potential anticancer therapy. In particular, it induces synergistic effects with other conventional therapies (such as chemo-, radio-, and photodynamic therapies) by regulating the activity of P-glycoprotein, acting as a vascular relaxant to relieve tumor hypoxia, and participating in the metabolism of reactive oxygen species. However, NO is highly reactive, and its half-life is relatively short after generation. Meanwhile, NO-induced anticancer activity is dose-dependent. Therefore, the targeted delivery of NO to the tumor is required for better therapeutic effects. In the past decade, NO-generating nanomedicines (NONs), which enable sustained and specific NO release in tumor tissues, have been developed for enhanced cancer therapy. This review describes the recent efforts and preclinical achievements in the development of NON-based cancer therapies. The chemical structures employed in the fabrication of NONs are summarized, and the strategies involved in NON-based cancer therapies are elaborated.
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Affiliation(s)
- Yuce Li
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Been Yoon
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Anup Dey
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Van Quy Nguyen
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea.; Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea.
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13
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PD-L1 rs2890658 Polymorphism Increases Risk for Non-Small-Cell Lung Cancer in Northern China Population Based on Experimental Data and Meta-Analysis. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:8433489. [PMID: 35992543 PMCID: PMC9363189 DOI: 10.1155/2022/8433489] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/25/2022] [Accepted: 07/01/2022] [Indexed: 11/18/2022]
Abstract
Purpose To dig the PD-L1 rs2890658 polymorphism with susceptibility of non-small-cell lung cancer (NSCLC) in northern China. Patients and Methods There were 600 NSCLC patients and 600 age and sex matched controls from the same ethnic origin recruited in the present research. Polymerase chain reaction-restriction fragment length polymorphism method genotyped PD-L1 rs2890658 polymorphism. PubMed and Embase were searched to get eligible literature for meta-analysis. The association between PD-L1 rs2890658 polymorphism and NSCLC risk was calculated with odds ratio and 95% confidence interval. Results It is more likely that individuals who have CC genotype and C allele are 2.15 and 1.41 times to develop NSCLC compared with individuals with AA genotype and A allele, respectively. Meta-analysis showed that the individuals who have C allele and CA genotype increased the risk of suffering from NSCLC. Conclusion PD-L1 rs2890658 polymorphism increased NSCLC risk in northern China population and it might predict the occurrence of NSCLC.
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14
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Hezave YA, Sharifi Z, Kermani FR, Shahabi M. Association of the rs4143815 polymorphism of PDL1 gene with HTLV-1 infection and proviral load in asymptomatic blood donors in northeast Iran. Microbiol Immunol 2022; 66:324-329. [PMID: 35289428 DOI: 10.1111/1348-0421.12976] [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: 12/01/2021] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 11/27/2022]
Abstract
Obviously, genetic differences, including mutations and polymorphisms, can play an important role in viral infections, So in this case-control study, which contained 81 Human T-cell leukemia virus type 1(HTLV-1) asymptomatic carriers (ACs) and 162 healthy controls (HCs), the rs4143815 polymorphism of PDL1 gene investigated. This polymorphism is the site of miR-570 binding and it can influence immune system responses. The rs4143815 polymorphism was evaluated by allele-specific polymerase chain reaction (AS-PCR) and proviral load (PVL) levels by quantitative real-time PCR (q PCR). The results demonstrated that C allele (p=0.027) and CC genotype (p=0.031) of rs4143815 polymorphism was significantly higher in ACs than HCs group also, the PVL in ACs with C allele (p=0.020) was higher significantly. Thus, the rs4143815 polymorphism can play a vital role in HTLV-1 infection. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Yalda Amiri Hezave
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Zohreh Sharifi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Fahime Ranjbar Kermani
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Majide Shahabi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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15
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Fan Z, Wu C, Chen M, Jiang Y, Wu Y, Mao R, Fan Y. The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation. Acta Pharm Sin B 2022; 12:1041-1053. [PMID: 35530130 PMCID: PMC9069407 DOI: 10.1016/j.apsb.2021.09.010] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/27/2021] [Accepted: 08/25/2021] [Indexed: 12/16/2022] Open
Abstract
The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.
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Key Words
- 3′-UTR, 3′-untranslated region
- ADAM17, a disintegrin and metalloprotease 17
- APCs, antigen-presenting cells
- AREs, adenylate and uridylate (AU)-rich elements
- ATF3, activating transcription factor 3
- CD273/274, cluster of differentiation 273/274
- CDK4, cyclin-dependent kinase 4
- CMTM6, CKLF like MARVEL transmembrane domain containing 6
- CSN5, COP9 signalosome subunit 5
- CTLs, cytotoxic T lymphocytes
- EMT, epithelial to mesenchymal transition
- EpCAM, epithelial cell adhesion molecule
- Exosome
- FACS, fluorescence-activated cell sorting
- GSDMC, Gasdermin C
- GSK3β, glycogen synthase kinase 3 beta
- HSF1, heat shock transcription factor 1
- Hi-C, high throughput chromosome conformation capture
- ICB, immune checkpoint blockade
- IFN, interferon
- IL-6, interleukin 6
- IRF1, interferon regulatory factor 1
- Immune checkpoint blockade
- JAK, Janus kinase 1
- NFκB, nuclear factor kappa B
- NSCLC, non-small cell lung cancer
- OTUB1, OTU deubiquitinase, ubiquitin aldehyde binding 1
- PARP1, poly(ADP-ribose) polymerase 1
- PD-1, programmed cell death-1
- PD-L1
- PD-L1, programmed death-ligand 1
- PD-L2
- PD-L2, programmed death ligand 2
- Post-transcriptional regulation
- Post-translational regulation
- SP1, specificity protein 1
- SPOP, speckle-type POZ protein
- STAG2, stromal antigen 2
- STAT3, signal transducer and activator of transcription 3
- T2D, type 2 diabetes
- TADs, topologically associating domains
- TFEB, transcription factor EB
- TFs, transcription factors
- TNFα, tumor necrosis factor-alpha
- TTP, tristetraprolin
- Topologically associating domain
- Transcription
- UCHL1, ubiquitin carboxy-terminal hydrolase L1
- USP22, ubiquitin specific peptidase 22
- dMMR, deficient DNA mismatch repair
- irAEs, immune related adverse events
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Affiliation(s)
- Zhiwei Fan
- Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, China
- Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China
| | - Changyue Wu
- Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China
- Department of Dermatology, Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, China
| | - Miaomiao Chen
- Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China
| | - Yongying Jiang
- Department of Pathophysiology, School of Medicine, Nantong University, Nantong 226001, China
| | - Yuanyuan Wu
- Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China
| | - Renfang Mao
- Department of Pathophysiology, School of Medicine, Nantong University, Nantong 226001, China
| | - Yihui Fan
- Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, China
- Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China
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16
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Hosseinzadeh R, Feizisani F, Shomali N, Abdelbasset WK, Hemmatzadeh M, Gholizadeh Navashenaq J, Jadidi-Niaragh F, Bokov DO, Janebifam M, Mohammadi H. PD-1/PD-L1 blockade: Prospectives for immunotherapy in cancer and autoimmunity. IUBMB Life 2021; 73:1293-1306. [PMID: 34538007 DOI: 10.1002/iub.2558] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 08/10/2021] [Accepted: 09/06/2021] [Indexed: 12/14/2022]
Abstract
Immune checkpoint blockade therapy (ICBT) has become a successful cancer treatment approach in the field of cancer immunotherapy. Blockade of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) with monoclonal antibodies have been known as successful examples of cancer immunotherapy in recent years. Although ICBT has been shown to be beneficial in cancers, such benefits have only been seen in a portion of cancer patients. In this regard, enhancing the therapeutic effects of inhibiting PD-1 and PD-L1 and reducing the side effects of this approach can be considered as a potential approach in a successful ICBT. In this review, we have highlighted new viewpoints regarding improving the therapeutic effect of PD-1 and PD-L1 blockades in cancer therapy. Besides, their expression levels as a biomarker with prognostic value, their role in intestinal microbiota modulation, combination therapy, and immune-related side effects (irAEs) have been discussed.
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Affiliation(s)
- Ramin Hosseinzadeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Feizisani
- Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran
| | - Navid Shomali
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia.,Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dmitry O Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation.,Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russian Federation
| | - Morteza Janebifam
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.,Noncommunicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
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17
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Dutta R, Khalil R, Mayilsamy K, Green R, Howell M, Bharadwaj S, Mohapatra SS, Mohapatra S. Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model. Front Immunol 2021; 12:706133. [PMID: 34381456 PMCID: PMC8350740 DOI: 10.3389/fimmu.2021.706133] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/25/2021] [Indexed: 01/10/2023] Open
Abstract
The axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5-10% of patients, the majority of the cohorts show resistance to this checkpoint blockade (CB) therapy. Multiple factors assist in the growth of resistance to CB, among which T cell exhaustion and immunosuppressive effects of immune cells in the tumor microenvironment (TME) play a critical role along with other tumor intrinsic factors. We have previously shown the polyketide antibiotic, Mithramycin-A (Mit-A), an effective agent in killing cancer stem cells (CSCs) in vitro and in vivo in a subcutaneous murine model. Since TME plays a pivotal role in CB therapy, we tested the immunomodulatory efficacy of Mit-A with anti-PD-L1 mAb (αPD-L1) combination therapy in an immunocompetent MC38 syngeneic orthotopic CRC mouse model. Tumors and spleens were analyzed by flow cytometry for the distinct immune cell populations affected by the treatment, in addition to RT-PCR for tumor samples. We demonstrated the combination treatment decreases tumor growth, thus increasing the effectiveness of the CB. Mit-A in the presence of αPD-L1 significantly increased CD8+ T cell infiltration and decreased immunosuppressive granulocytic myeloid-derived suppressor cells and anti-inflammatory macrophages in the TME. Our results revealed Mit-A in combination with αPD-L1 has the potential for augmented CB therapy by turning an immunologically "cold" into "hot" TME in CRC.
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Affiliation(s)
- Rinku Dutta
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Roukiah Khalil
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Karthick Mayilsamy
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Ryan Green
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Mark Howell
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Srinivas Bharadwaj
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Shyam S. Mohapatra
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Subhra Mohapatra
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Center for Research and Education in Nano-Bioengineering, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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19
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da Silva MC, Medeiros FS, da Silva NCH, Paiva LA, Gomes FODS, Costa E Silva M, Gomes TT, Peixoto CA, Rygaard MCV, Menezes MLB, Welkovic S, Donadi EA, Lucena-Silva N. Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 ( PDCD1) rs36084323 A Allele in a Dominant Model. Front Cell Infect Microbiol 2021; 11:587932. [PMID: 34290992 PMCID: PMC8288189 DOI: 10.3389/fcimb.2021.587932] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 04/21/2021] [Indexed: 11/16/2022] Open
Abstract
The high-risk oncogenic human papillomavirus (HPV) has developed mechanisms for evasion of the immune system, favoring the persistence of the infection. The chronic inflammation further contributes to the progression of tissue injury to cervical cancer. The programmed cell death protein (PD-1) after contacting with its ligands (PD-L1 and PD-L2) exerts an inhibitory effect on the cellular immune response, maintaining the balance between activation, tolerance, and immune cell-dependent lesion. We evaluated 295 patients exhibiting or not HPV infection, stratified according to the location (injured and adjacent non-injured areas) and severity of the lesion (benign, pre-malignant lesions). Additionally, we investigated the role of the promoter region PDCD1 -606G>A polymorphism (rs36084323) on the studied variables. PD-1 and PDCD1 expression were evaluated by immunohistochemistry and qPCR, respectively, and the PDCD1 polymorphism was evaluated by nucleotide sequencing. Irrespective of the severity of the lesion, PD-1 levels were increased compared to adjacent uninjured areas. Additionally, in cervical intraepithelial neoplasia (CIN) I, the presence of HPV was associated with increased (P = 0.0649), whereas in CIN III was associated with decreased (P = 0.0148) PD-1 levels, compared to the uninjured area in absence of HPV infection. The PDCD1 -606A allele was rare in our population (8.7%) and was not associated with the risk for development of HPV infection, cytological and histological features, and aneuploidy. In contrast, irrespective of the severity of the lesion, patients exhibiting the mutant PDCD1 -606A allele at single or double doses exhibited increased protein and gene expression when compared to the PDCD1 -606GG wild type genotype. Besides, the presence of HPV was associated with the decrease in PDCD1 expression and PD-1 levels in carriers of the -606 A allele presenting severe lesions, suggesting that other mediators induced during the HPV infection progression may play an additional role. This study showed that increased PD-1 levels are influenced by the -606G>A nucleotide variation, particularly in low-grade lesions, in which the A allele favors increased PDCD1 expression, contributing to HPV immune system evasion, and in the high-grade lesion, by decreasing tissue PD-1 levels.
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Affiliation(s)
- Mauro César da Silva
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | - Fernanda Silva Medeiros
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | | | | | | | - Matheus Costa E Silva
- Clinical Immunology Division, Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil
| | - Thailany Thays Gomes
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | - Christina Alves Peixoto
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | | | | | - Stefan Welkovic
- Integrated Health Center Amaury de Medeiros (CISAM), University of Pernambuco, Recife, Brazil
| | - Eduardo Antônio Donadi
- Clinical Immunology Division, Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil
| | - Norma Lucena-Silva
- Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil.,Laboratory of Molecular Biology, IMIP Hospital, Pediatric Oncology Service, Recife, Brazil
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20
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Minari R, Bonatti F, Mazzaschi G, Dodi A, Facchinetti F, Gelsomino F, Cinquegrani G, Squadrilli A, Bordi P, Buti S, Bersanelli M, Leonetti A, Cosenza A, Ferri L, Rapacchi E, Quaini F, Ardizzoni A, Tiseo M. PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors. TUMORI JOURNAL 2021; 108:47-55. [PMID: 34002648 DOI: 10.1177/03008916211014954] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To investigate the role of CTLA-4, PD-1 (programmed death-1), and PD-L1 (programmed death-ligand 1) single nucleotide polymorphisms (SNPs) in predicting clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). METHODS A total of 166 consecutive patients were included. We correlated SNPs with clinical benefit, progression-free survival, time to treatment failure, and overall survival and evaluated the incidence of SNPs in nonresponder and long clinical benefit groups. RESULTS Considering the entire cohort, no correlation was found between SNPs and clinical outcome; however, PD-L1 rs4143815 SNP and the long clinical benefit group showed a statistically significant association (p = 0.02). The nonresponder cohort displayed distinctive PD-L1 haplotype (p = 0.05). CONCLUSION PD-L1 SNPs seem to be marginally involved in predicting clinical outcome of NSCLC treated with ICI, but further investigations are required.
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Affiliation(s)
- Roberta Minari
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Giulia Mazzaschi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine & Surgery, University of Parma
| | | | - Francesco Facchinetti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy.,Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France
| | | | | | - Anna Squadrilli
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Paola Bordi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Agnese Cosenza
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Leonarda Ferri
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Elena Rapacchi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Andrea Ardizzoni
- Medical Oncology, AOU Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Marcello Tiseo
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy.,Department of Medicine & Surgery, University of Parma
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21
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Machado-Rugolo J, Gutierrez Prieto T, Fabro AT, Parra Cuentas ER, Sá VK, Baldavira CM, Rainho CA, Castelli EC, Farhat C, Takagaki TY, Nagai MA, Capelozzi VL. Relevance of PD-L1 Non-Coding Polymorphisms on the Prognosis of a Genetically Admixed NSCLC Cohort. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:239-252. [PMID: 33623414 PMCID: PMC7894801 DOI: 10.2147/pgpm.s286717] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/14/2021] [Indexed: 12/25/2022]
Abstract
Purpose Although non-small cell lung cancer (NSCLC) remains a deadly disease, new predictive biomarkers have emerged to assist in managing the disease, of which one of the most promising is the programmed death‐ligand 1 (PD-L1). Each, PD-L1 variant seem to modulate the function of immune checkpoints differently and affect response to adjuvant treatment and outcome in NSCLC patients. We thus investigated the influence of these PD-L1 genetic variations in genetically admixed NSCLC tissue samples, and correlated these values with clinicopathological characteristics, including prognosis. Materials and Methods We evaluated PD-L1 non-coding genetic variants and protein expression in lung adenocarcinomas (ADC), squamous cell carcinomas (SqCC), and large cell carcinomas (LCC) in silico. Microarray paraffin blocks from 70 samples of ADC (N=33), SqCC (N=24), and LCC (N=13) were used to create PD-L1 multiplex immunofluorescence assays with a Cell Signaling E1L3N clone. Fifteen polymorphisms of the PD-L1 gene were investigated by targeted sequencing and evaluated in silico using dedicated tools. Results Although PD-L1 polymorphisms seemed not to interfere with protein expression, PD-L1 expression varied among different histological subtypes, as did clinical outcomes, with the rs4742098A>G, rs4143815G>C, and rs7041009G>A variants being associated with relapse (P=0.01; P=0.05; P=0.02, respectively). The rs7041009 GG genotype showed a significant correlation with younger and alive patients compared to carriers of the A allele (P=0.02 and P<0.01, respectively). The Cox regression model showed that the rs7041009 GG genotype may influence OS (P<0.01) as a co-dependent factor associated with radiotherapy and recurrence in NSCLC patients. Furthermore, the Kaplan–Meier survival curves showed that rs7041009 and rs4742098 might impact PPS in relapsed patients. In silico approaches identified the variants as benign. Conclusion PD-L1 non-coding variants play an important role in modulating immune checkpoint function and may be explored as immunotherapy biomarkers. We highlight the rs7041009 variant, which impacts OS and PPS in NSCLC patients.
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Affiliation(s)
- Juliana Machado-Rugolo
- Laboratory of Genomics and Histomorphometry, Department of Pathology, University of São Paulo Medical School (USP), São Paulo, Brazil.,Health Technology Assessment Center, Clinical Hospital (HCFMB), Medical School of São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Tabatha Gutierrez Prieto
- Laboratory of Genomics and Histomorphometry, Department of Pathology, University of São Paulo Medical School (USP), São Paulo, Brazil
| | - Alexandre Todorovic Fabro
- Department of Pathology and Legal Medicine, Ribeirão Preto School of Medicine, University of São Paulo (FMRP-USP), Ribeirão Preto, Brazil
| | - Edwin Roger Parra Cuentas
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Vanessa Karen Sá
- Laboratory of Genomics and Molecular Biology, Centro Internacional De Pesquisa (CIPE), AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Camila Machado Baldavira
- Laboratory of Genomics and Histomorphometry, Department of Pathology, University of São Paulo Medical School (USP), São Paulo, Brazil
| | - Claudia Aparecida Rainho
- Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Erick C Castelli
- Molecular Genetics and Bioinformatics Laboratory, Experimental Research Unit (UNIPEX), Medical School of São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.,Department of Pathology, Medical School of São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Cecilia Farhat
- Laboratory of Genomics and Histomorphometry, Department of Pathology, University of São Paulo Medical School (USP), São Paulo, Brazil
| | - Teresa Yae Takagaki
- Division of Pneumology, Heart Institute (Incor), Clinical Hospital, University of São Paulo Medical School (USP), São Paulo, São Paulo, Brazil
| | - Maria Aparecida Nagai
- Department of Radiology and Oncology, University of São Paulo Medical School (USP), São Paulo, Brazil.,Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo (ICESP), São Paulo, Brazil
| | - Vera Luiza Capelozzi
- Laboratory of Genomics and Histomorphometry, Department of Pathology, University of São Paulo Medical School (USP), São Paulo, Brazil
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22
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Meng F, Yang M, Chen Y, Chen W, Wang W. miR-34a induces immunosuppression in colorectal carcinoma through modulating a SIRT1/NF-κB/B7-H3/TNF-α axis. Cancer Immunol Immunother 2021; 70:2247-2259. [PMID: 33492448 DOI: 10.1007/s00262-021-02862-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 01/15/2021] [Indexed: 12/14/2022]
Abstract
Although a number of studies have revealed the important roles of miR-34a in cancer, the regulatory roles of miR-34a in cancer immune response remain largely unknown. Our present study demonstrated a mechanism underlying miR-34a-mediated cancer immune evasion via a SIRT1/NF-κB/B7-H3/TNF-α axis. miR-34a upregulated B7-H3, an important immune checkpoint molecule, through direct inhibition of SIRT1 and consequent acetylation of NF-κB subunit p65 (a-p65), which promoted B7-H3 transcription by direct binding to its promoter. The elevated B7-H3 induced production of pro-inflammatory cytokines including TNF-α. This was further confirmed in the colon of Mir34a-deficient mice, where Sirt1 expression was boosted, and the expressions of a-p65, B7h3, and Tnf were repressed. Consequently, the in vivo inhibitory activity of miR-34a on colorectal cancer (CRC) was eradicated by the reinforced B7-H3 and TNF-α. In conclusion, our study uncovered an etiological mechanism underlying miR-34a-mediated CRC immune evasion through inhibition of SIRT1 and promotion of NF-κB/B7-H3/TNF-α axis.
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Affiliation(s)
- Fanyi Meng
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Yinshuang Chen
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Weichang Chen
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China. .,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Yunxuan Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China.
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23
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Wagner M, Jasek M, Karabon L. Immune Checkpoint Molecules-Inherited Variations as Markers for Cancer Risk. Front Immunol 2021; 11:606721. [PMID: 33519815 PMCID: PMC7840570 DOI: 10.3389/fimmu.2020.606721] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022] Open
Abstract
In recent years, immunotherapy has been revolutionized by a new approach that works by blocking receptors called immune checkpoints (IC). These molecules play a key role in maintaining immune homeostasis, mainly by suppressing the immune response and by preventing its overactivation. Since inhibition of the immune response by IC can be used by cancer to avoid recognition and destruction by immune system, blocking them enhances the anti-tumor response. This therapeutic approach has brought spectacular clinical effects. The ICs present heterogeneous expression patterns on immune cells, which may affect the effectiveness of immunotherapy. The inherited genetic variants in regulatory regions of ICs genes can be considered as potential factors responsible for observed inter-individual differences in ICs expression levels on immune cells. Additionally, polymorphism located in exons may introduce changes to ICs amino acid sequences with potential impact on functional properties of these molecules. Since genetic variants may affect both expression and structure of ICs, they are considered as risk factors of cancer development. Inherited genetic markers such as SNPs may also be useful in stratification patients into groups which will benefit from particular immunotherapy. In this review, we have comprehensively summarized the current understanding of the relationship between inherited variations of CTLA-4, PDCD1, PD-L1, BTLA, TIM-3, and LAG-3 genes in order to select SNPs which can be used as predictive biomarkers in personalized evaluation of cancer risk development and outcomes as well as possible response to immunotherapy.
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Affiliation(s)
| | - Monika Jasek
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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24
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Relationship of PD-1 (PDCD1) and PD-L1 (CD274) Single Nucleotide Polymorphisms with Polycystic Ovary Syndrome. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9596358. [PMID: 33521133 PMCID: PMC7817229 DOI: 10.1155/2021/9596358] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 11/30/2020] [Accepted: 12/18/2020] [Indexed: 12/13/2022]
Abstract
This study is to investigate the relationship of programmed cell death 1 (PD-1; also known as PDCD1) and programmed death-1-ligand 1 (PD-L1; also known as CD274) single nucleotide polymorphisms (SNPs) with polycystic ovary syndrome (PCOS). This study enrolled 330 PCOS patients and 350 matched controls. ELISA was used to detect the PD-1 and PD-L1 levels in serum. SnaPshot genotyping was performed to analyze the PD-1 and PD-L1 genotyping. Linkage disequilibrium and haplotype of TagSNP loci of PD-1 and PD-L1 genes were also detected. The relationship of genotypes and alleles with PCOS was analyzed. The levels of PD-1 and PD-L1 in the serum of PCOS patients were significantly lower than those in the control group (P < 0.01). The haplotype TT of PD-1 gene at rs10204525 and rs7421861 loci was significantly lower in the PCOS group than in the control group (P < 0.001, OR = 0.67, and 95%CI = 0.54‐0.84). PD-L1 gene SNP loci rs2282055, rs2890658, rs10125854, and rs702275 had linkage disequilibrium. The haplotypes TAAA, GAAC, GAGC, GCAA, and TCGA of PD-L1 gene SNP loci were significantly higher in PCOS patients than in the control group, whereas haplotypes GAAA, TAAC, TCAA, GCGA, GCAC, and TCGC of PD-L1 gene SNP loci were significantly lower in PCOS patients than in the control group. PD-1 and PD-L1 SNPs may be related to the pathogenesis of PCOS. PD-1 gene SNP loci rs10204525 and rs7421861 and PD-L1 gene SNP loci rs2282055, rs2890658, rs10125854, and rs702275 may be new candidate polymorphic loci for PCOS.
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25
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Yoshida H, Nomizo T, Ozasa H, Tsuji T, Funazo T, Yasuda Y, Ajimizu H, Yamazoe M, Kuninaga K, Ogimoto T, Hosoya K, Itotani R, Sakamori Y, Kim YH, Hirai T. PD-L1 polymorphisms predict survival outcomes in advanced non-small-cell lung cancer patients treated with PD-1 blockade. Eur J Cancer 2020; 144:317-325. [PMID: 33385948 DOI: 10.1016/j.ejca.2020.11.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/13/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. METHODS PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. RESULTS Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18-0.64; p = 0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31-1.70; p = 0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. CONCLUSIONS PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status.
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Affiliation(s)
- Hironori Yoshida
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Takashi Nomizo
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Hiroaki Ozasa
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan.
| | - Takahiro Tsuji
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Tomoko Funazo
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Yuto Yasuda
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Hitomi Ajimizu
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Masatoshi Yamazoe
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Kiyomitsu Kuninaga
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Tatsuya Ogimoto
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Kazutaka Hosoya
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Ryo Itotani
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Yuichi Sakamori
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Japan
| | - Young Hak Kim
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Toyohiro Hirai
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan
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26
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Yang Z, Gao D, Guo X, Jin L, Zheng J, Wang Y, Chen S, Zheng X, Zeng L, Guo M, Zhang X, Tian Z. Fighting Immune Cold and Reprogramming Immunosuppressive Tumor Microenvironment with Red Blood Cell Membrane-Camouflaged Nanobullets. ACS NANO 2020; 14:17442-17457. [PMID: 33166111 DOI: 10.1021/acsnano.0c07721] [Citation(s) in RCA: 187] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Nanomedicine, acting as the magic bullet, is capable of combining immunotherapy with other treatments to reverse a cold tumor (immune depletion) into a hot tumor. However, how to comprehensively inhibit the immunosuppressive tumor microenvironment (TME) remains a major challenge for immunotherapy to achieve the maximum benefits. Thus, a strategy that can simultaneously increase the recruitment of tumor infiltrating lymphocytes (TILs) and comprehensively reprogram the immunosuppressive TME is still urgently needed. Herein, a thermal-sensitive nitric oxide (NO) donor S-nitrosothiols (SNO)-pendant copolymer (poly(acrylamide-co-acrylonitrile-co-vinylimidazole)-SNO copolymer, PAAV-SNO) with upper critical solution temperature (UCST) was synthesized and employed to fabricate an erythrocyte membrane-camouflaged nanobullet for codelivery of NIR II photothermal agent IR1061 and indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan (1-MT). This multifunctional nanobullet possessed long circulation in vivo, enhanced accumulation at the tumor site, and therapeutics-controlled release by NIR II laser, thereby it could avoid unspecific drug leakage while enhancing biosecurity. More importantly, the immunogenic cell death (ICD) induced by local hyperthermia from photothermal therapy (PTT) could be conducive for the increased recruitment of CD8+ cytotoxic T lymphocytes (CTLs) at the tumor site. Furthermore, through interfering in the IDO-1 activity by 1-MT and normalizing the tumor vessels by in situ generated NO, the immunosuppressive TME was comprehensively reprogrammed toward an immunostimulatory phenotype, achieving the excellent therapeutic efficacy against both primary breast cancer and metastases. Collectively, this multifunctional nanobullet described in this study developed an effective and promising strategy to comprehensively reprogram suppressive TME and treat "immune cold" tumors.
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Affiliation(s)
- Zhe Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Di Gao
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Xiaoqing Guo
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Lin Jin
- International Joint Research Laboratory for Biomedical Nanomaterials of Henan, Zhoukou Normal University, Zhoukou 466001, P. R. China
| | - Juanjuan Zheng
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, United States
| | - Ying Wang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Shuojia Chen
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Xuewei Zheng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Li Zeng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Ming Guo
- School of Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Xingcai Zhang
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, United States
- School of Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Zhongmin Tian
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
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27
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Zhao Q, Guo J, Zhao Y, Shen J, Kaboli PJ, Xiang S, Du F, Wu X, Li M, Wan L, Li X, Wen Q, Li J, Zou C, Xiao Z. Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers. Epigenomics 2020; 12:2155-2171. [PMID: 33337915 DOI: 10.2217/epi-2020-0093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.
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Affiliation(s)
- Qijie Zhao
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Jinan Guo
- The department of urology, The Second Clinical Medical college of Jinan University (Shenzhen people's Hospital), The First Affiliated Hospital of South University of Science & Technology of China, Shenzhen Urology Minimally Invasive Engineering Center, Shenzhen, Guangdong, PR China.,Shenzhen Public Service Platform on Tumor Precision Medicine & Molecular Diagnosis, Shenzhen, Guangdong, PR China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
| | - Parham Jabbarzadeh Kaboli
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
| | - Shixin Xiang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
| | - Lin Wan
- Department of Hematology & Oncology, The Children's Hospital of Soochow, Jiangsu, PR China
| | - Xiang Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China
| | - Jing Li
- Department of Oncology & Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, Sichuan, PR China
| | - Chang Zou
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, PR China.,Shenzhen Public Service Platform on Tumor Precision Medicine & Molecular Diagnosis, Shenzhen, Guangdong, PR China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, PR China
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SNP-SNP Interaction in Genes Encoding PD-1/PD-L1 Axis as a Potential Risk Factor for Clear Cell Renal Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12123521. [PMID: 33255938 PMCID: PMC7760680 DOI: 10.3390/cancers12123521] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Immune checkpoints are key receptors that regulate the immune system and prevent its overactivation. This regulatory mechanism, which under normal conditions is responsible for maintaining immune homeostasis, can be misused by cancer cells, allowing them to avoid recognition and destruction. PD-1 is one of the major immune checkpoints that when interacting with its ligands—PD-L1/PD-L2, regulates the immune surveillance in the tumor microenvironment. We therefore hypothesized that single nucleotide polymorphisms (SNPs) (located in regulatory regions involved in regulation of expression and alternative splicing as well as SNPs introducing changes to the protein sequence) in genes encoding PD-1 and PD-L1 molecules may be associated with the development and outcome of renal cell carcinoma (RCC). We genotyped nine SNPs in PD-1/PD-L1 axis genes, with application of TaqMan allelic discrimination assays, and found that two of them taken together (rs10815225xrs7421861) may be considered to be potential risk factor for clear cell RCC. Abstract PD-1/PD-L1 axis plays an important role in maintaining homeostasis and prevention from autoimmunity; however, in the tumor microenvironment, PD-1/PD-L1 interaction is responsible for the evasion of immune surveillance by tumor cells. We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 and PD-L1 molecules are associated with the development and outcome of renal cell carcinoma (RCC). Here we genotyped nine polymorphisms: five of PDCD1: rs36084323G>A, rs11568821G>A, rs2227981C>T, rs10204525G>A, rs7421861T>C and four of PD-L1: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C in 237 RCC patients (including 208 with clear cell RCC (ccRCC)) and 256 controls, with application of allelic discrimination method with use of TaqMan Assays. Interestingly, we found the SNP-SNP interaction between rs10815225 and rs7421861 polymorphisms associated with ccRCC risk. The rs7421861 TC genotype decreased the risk of ccRCC development compared to TT and CC genotypes in the group of rs10815225 GC + CC individuals (OR = 0.21, CI95% = 0.08; 0.54). While possessing of rs10815225 GC or CC genotype increased susceptibility to ccRCC when compared to rs10815225 GG genotype in individuals with rs7421861 TT or CC genotype (OR = 2.40, CI95% = 1.25; 4.61). In conclusion, genetic variants in PDCD1 and PD-L1 genes, especially taken together as SNP-SNP interactions, can be considered to be ccRCC risk factors.
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Lu J, Wu Z, Peng J, Xu S, Zhou L, Lin Y, Wang Y, Yin W, Lu J. Programmed death-ligand 1 single nucleotide polymorphism affects breast cancer chemosensitivity and adverse events in the neoadjuvant setting. Int J Biol Markers 2020; 35:90-101. [PMID: 33073683 DOI: 10.1177/1724600820926172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE We aimed to determine whether single nucleotide polymorphisms in the PD-L1 gene are related to the response and adverse events of patients receiving neoadjuvant therapy and to explore the mechanism. METHODS Nine single nucleotide polymorphisms of PD-L1 were selected and tested among patients before neoadjuvant therapy. Four models were used in single nucleotide polymorphism genotype analysis: the addictive model compared TT vs TA vs AA; the dominant model compared TT vs TA+AA; the recessive model compared TT+TA vs AA; and the over-dominant model compared TT+AA vs TA (A as the minor allele). We analyzed the associations between single nucleotide polymorphism genotypes and pathological complete response, disease-free survival, and adverse events. Overexpression of the targeted microRNA was carried out using microRNA mimics. Logistic regression was used to analyze the associations between different single nucleotide polymorphism genotypes and pathological complete response outcome. Kaplan-Meier plots and log-rank tests were used to compare disease-free survival between groups with different single nucleotide polymorphism genotypes. The Cox proportional hazards model was used to calculate the adjusted hazard ratio. The Spearman's correlation test was used to determine the correlations between different genotypes and adverse events. RESULTS rs4143815C>G was associated with better pathological complete response in the addictive and over-dominant models and with poorer disease-free survival in the recessive model. Patients with different genotypes had different adverse events. Overexpression of miR34c resulted in the downregulation of PD-L1 mRNA expression. CONCLUSION The PD-L1 single nucleotide polymorphism rs4143815 was associated with the pathological complete response rate, disease-free survival, and adverse events in breast cancer patients receiving neoadjuvant therapy. The interaction between miR34c and PD-L1 might be affected by rs4143815.
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Affiliation(s)
- Jinglu Lu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Ziping Wu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Shuguang Xu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Liheng Zhou
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Yanping Lin
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Yan Wang
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Wenjin Yin
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
| | - Jinsong Lu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *Authors contributed equally
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Youssef N, Noureldein M, Daoud G, Eid AA. Immune checkpoint inhibitors and diabetes: Mechanisms and predictors. DIABETES & METABOLISM 2020; 47:101193. [PMID: 33010422 DOI: 10.1016/j.diabet.2020.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/23/2020] [Accepted: 09/19/2020] [Indexed: 02/07/2023]
Abstract
The emergence of immune checkpoint inhibitors in the arsenal of cancer immunotherapy was a breakthrough which provided hope to many cancer patients. However, not long has passed since their discovery that some adverse effects were associated with these promising therapeutic agents. Immune checkpoint inhibitors dysregulate host immunity and may precipitate autoimmune diseases including diabetes mellitus. In this review, we go beyond the case reports towards understanding the underlying mechanisms by which Programmed cell death 1 (PD-1) and Programmed death ligand-1 (PD-L1) inhibitors precipitate diabetes. We discuss the role of PD-1/PD-L1 in autoimmunity and the use of mice models to describe their involvement in diabetes. We also reviewed the genetic anomalies in PD-1/PD-L1genes and their link to diabetes. Finally, we present the studies conducted to identify patients at risk of developing autoimmune diseases as an adverse effect for PD-1/PD-L1 use. Understanding these issues can guide researchers to find a way to circumvent the autoimmune adverse reactions seen with PD-1/PD-L1 inhibitors without affecting their antitumor activity.
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Affiliation(s)
- Natalie Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Centre, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon
| | - Mohamed Noureldein
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Centre, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon
| | - Georges Daoud
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Centre, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Centre, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon.
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31
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Kula A, Dawidowicz M, Kiczmer P, Prawdzic Seńkowska A, Świętochowska E. The role of genetic polymorphism within PD-L1 gene in cancer. Review. Exp Mol Pathol 2020; 116:104494. [PMID: 32679050 DOI: 10.1016/j.yexmp.2020.104494] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/11/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023]
Abstract
The maintenance of homeostasis of the immune system depends on the balance between excitatory and inhibitory signals. Programmed death ligand (PD-L1) is a molecule which downregulates the immune system targeting the programmed death receptor 1 (PD-1). Under physiological conditions, the receptor is constitutively expressed in lymphocytes. The PD-L1 / PD-1 pathway plays a key role in completing the immune response in the right way, preventing excessive stimulation of the cells of the immune system, protecting the organism against autoimmunity. Under pathological conditions PD-L1 expression may take place in tumor cells. Binding of PD-1 to its ligand on tumor cells suppresses T lymphocytes through a negative feedback. This mechanism allows abnormal cells to avoid destruction by the host immune system. The expression of PD-L1 in tumors has been described in many histological types of cancer: melanoma, lung cancer, breast and ovarian, pancreatic and esophagus adenocarcinoma, kidney tumors and bladder cancers as well as in hematopoietic malignancies. Many studies report a significant effect of PD-L1 polymorphisms on clinical parameters of patients. Studies of PD-L1 polymorphisms showed their influence on the stage of cancer, effectiveness of chemotherapy and prognosis after tumor resection. Further analysis of the polymorphisms may result in development of effective therapies that restore anti-tumor immunity. Inhibition of PD-L1 / PD-1 is one of the most promising immunotherapies for various types of cancer. This work was intended to present information about the impact of PD-L1 gene expression and polymorphisms on the clinical parameters of patients with cancer.
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Affiliation(s)
- Agnieszka Kula
- Department of Medical and Molecular Biology, Medical University of Silesia, Faculty of Medical Sciences in Zabrze, Poland.
| | - Miriam Dawidowicz
- Department of Medical and Molecular Biology, Medical University of Silesia, Faculty of Medical Sciences in Zabrze, Poland
| | - Paweł Kiczmer
- Department of Medical and Molecular Biology, Medical University of Silesia, Faculty of Medical Sciences in Zabrze, Poland
| | - Alicja Prawdzic Seńkowska
- Department of Medical and Molecular Biology, Medical University of Silesia, Faculty of Medical Sciences in Zabrze, Poland
| | - Elżbieta Świętochowska
- Department of Medical and Molecular Biology, Medical University of Silesia, Faculty of Medical Sciences in Zabrze, Poland
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Kono K, Nakajima S, Mimura K. Current status of immune checkpoint inhibitors for gastric cancer. Gastric Cancer 2020; 23:565-578. [PMID: 32468420 DOI: 10.1007/s10120-020-01090-4] [Citation(s) in RCA: 154] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
Recent breakthrough results from immune checkpoint inhibitors (ICI) have paved the way to a new era of cancer immunotherapy. In particular, inhibition of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis with ICI including nivolumab and pembrolizumab has been emerging as a novel treatment strategy for advanced gastric cancers (GC). In a meta-analysis for anti-PD-1/PD-L1 therapy in GC, the objective response rate was 12.0% and the disease control ratio was 34.7%. The ICI treatment in GC provided modest survival benefit and especially, anti-PD-1 treatment could improve the 12-month and 18-month overall survival rate and prolonged the duration of the response. Moreover, it is likely that anti-PD-1/PD-L1 therapy is more effective in subgroups with microsatellite instability-high, Epstein-Barr virus-positive or high mutation burden in advanced GC. The next steps for developing ICI in GC are mainly two challenges as follows. First is the identification of accurate biomarkers that can predict the response to ICI. The second challenge is the clinical development of combinatorial approaches to maximize the efficacy of ICI. In this review, recent advances in ICI for GC are discussed from a viewpoint of translational aspect including biomarkers and tumor microenvironment, and from a viewpoint of clinical aspects including combination therapies.
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Affiliation(s)
- Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
- Department of Medical Electrophysiology, Fukushima Medical University School of Medicine, Fukushima-city, Fukushima, 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-city, Fukushima, 960-1295, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima-city, Fukushima, 960-1295, Japan
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Karki K, Wright GA, Mohankumar K, Jin UH, Zhang XH, Safe S. A Bis-Indole-Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Antitumor Immunity. Cancer Res 2020; 80:1011-1023. [PMID: 31911554 PMCID: PMC7056589 DOI: 10.1158/0008-5472.can-19-2314] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 09/20/2019] [Accepted: 01/03/2020] [Indexed: 12/31/2022]
Abstract
PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells, PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal germinal center (GC)-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole-derived NR4A1 antagonists including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoter-dependent luciferase activity, and protein. In in vivo studies using a syngeneic mouse model bearing orthotopically injected 4T1 cells, Cl-OCH3 decreased tumor growth and weight and inhibited lung metastasis. Cl-OCH3 also decreased expression of CD3+/CD4+/CD25+/FoxP3+ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anticancer activities of NR4A1 antagonists are also accompanied by enhanced antitumor immunity in PD-L1-expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy. SIGNIFICANCE: These findings show that the orphan nuclear receptor NR4A1 controls PD-L1 expression and identify a chemical probe capable of disrupting this regulatory axis.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- B7-H1 Antigen/immunology
- B7-H1 Antigen/metabolism
- Cell Line, Tumor/transplantation
- Disease Models, Animal
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Immunotherapy/methods
- Indoles/pharmacology
- Indoles/therapeutic use
- Lung Neoplasms/immunology
- Lung Neoplasms/prevention & control
- Lung Neoplasms/secondary
- Mice
- Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Proteolysis/drug effects
- T-Lymphocytes, Cytotoxic/drug effects
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- Triple Negative Breast Neoplasms/drug therapy
- Triple Negative Breast Neoplasms/immunology
- Triple Negative Breast Neoplasms/pathology
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/immunology
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Affiliation(s)
- Keshav Karki
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Gus A Wright
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas
| | - Kumaravel Mohankumar
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Un-Ho Jin
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Xing-Han Zhang
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
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Yasuda Y, Tokunaga K, Koga T, Sakamoto C, Goldberg IG, Saitoh N, Nakao M. Computational analysis of morphological and molecular features in gastric cancer tissues. Cancer Med 2020; 9:2223-2234. [PMID: 32012497 PMCID: PMC7064096 DOI: 10.1002/cam4.2885] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/13/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
Biological morphologies of cells and tissues represent their physiological and pathological conditions. The importance of quantitative assessment of morphological information has been highly recognized in clinical diagnosis and therapeutic strategies. In this study, we used a supervised machine learning algorithm wndchrm to classify hematoxylin and eosin (H&E)‐stained images of human gastric cancer tissues. This analysis distinguished between noncancer and cancer tissues with different histological grades. We then classified the H&E‐stained images by expression levels of cancer‐associated nuclear ATF7IP/MCAF1 and membranous PD‐L1 proteins using immunohistochemistry of serial sections. Interestingly, classes with low and high expressions of each protein exhibited significant morphological dissimilarity in H&E images. These results indicated that morphological features in cancer tissues are correlated with expression of specific cancer‐associated proteins, suggesting the usefulness of biomolecular‐based morphological classification.
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Affiliation(s)
- Yoko Yasuda
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.,Department of Health Science, Faculty of Medical Science, Kyushu University, Fukuoka, Japan
| | - Kazuaki Tokunaga
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Tomoaki Koga
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Chiyomi Sakamoto
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Ilya G Goldberg
- Image Informatics and Computational Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | | | - Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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35
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Venugopal G, O'Regan NL, Babu S, Schumann RR, Srikantam A, Merle R, Hartmann S, Steinfelder S. Association of a PD-L2 Gene Polymorphism with Chronic Lymphatic Filariasis in a South Indian Cohort. Am J Trop Med Hyg 2019; 100:344-350. [PMID: 30594267 DOI: 10.4269/ajtmh.18-0731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Lymphatic filariasis (LF) is a parasitic infection, caused by three closely related nematodes, namely Wuchereria bancrofti, Brugia malayi, and Brugia timori. Previously, we have shown that lysate from B. malayi microfilariae induces the expression of interleukin (IL)-10 and programmed death-ligand (PD-L) 1 on monocytes, which lead to inhibition of CD4+ T-cell responses. In this study, we investigated associations of IL-10 and programmed cell death (PD)-1 pathway gene polymorphisms with clinical manifestation in LF. We evaluated the frequency of alleles and genotypes of IL-10 (rs3024496, rs1800872), IL-10RA (rs3135932), IL-10RB (rs2834167), PD-1 (rs2227982, rs10204525), PD-L1 (rs4143815), PD-L2 (rs7854413), and single-nucleotide polymorphisms (SNPs) in 103 patients with chronic pathology (CP), such as elephantiasis or hydrocele and 106 endemic normal (EN) individuals from a South Indian population living in an area endemic for LF. Deviations from the Hardy-Weinberg equilibrium were tested, and we found a significant difference between the frequency of polymorphisms in PD-L2 (rs7854413; P < 0.001) and IL-10RB (rs2834167; P = 0.012) between the CP and the EN group, whereas there were no significant differences found among IL-10, IL-10RA, PD-1, and PD-L1 SNPs. A multivariate analysis showed that the existence of a CC genotype in PD-L2 SNP rs7854413 is associated with a higher risk of developing CP (OR: 2.942; 95% confidence interval [CI]: 0.957-9.046; P = 0.06). Altogether, these data indicate that a genetically determined individual difference in a non-synonymous missense SNP of PD-L2 might influence the susceptibility to CP.
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Affiliation(s)
- Gopinath Venugopal
- Centre for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany
| | - Noëlle L O'Regan
- Centre for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany
| | - Subash Babu
- National Institutes of Health, National Institute of Research in Tuberculosis (NIRT), International Centre for Excellence in Research, Chennai, India
| | - Ralf R Schumann
- Institute for Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Aparna Srikantam
- Blue Peter Public Health and Research Centre, LEPRA Society, Hyderabad, India
| | - Roswitha Merle
- Department of Veterinary Medicine, Institute for Veterinary Epidemiology and Biostatistics, Freie Universität Berlin, Berlin, Germany
| | - Susanne Hartmann
- Centre for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany
| | - Svenja Steinfelder
- Centre for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany.,Department of Neural Circuits and Behavior, Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Basis of PD1/PD-L1 Therapies. J Clin Med 2019; 8:jcm8122168. [PMID: 31817953 PMCID: PMC6947170 DOI: 10.3390/jcm8122168] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/02/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023] Open
Abstract
It is obvious that tumor cells have developed a number of strategies to escape immune surveillance including an altered expression of various immune checkpoints, such as the programmed death-1 receptor (PD-1) and its ligands PD-L1 and PD-L2. The interaction between PD-1 and PD-L1 results in an activation of self-tolerance pathways in both immune cells as well as tumor cells. Thus, these molecules represent excellent targets for T cell-based immunotherapies. However, the efficacy of therapies using checkpoint inhibitors is variable and only a limited number of patients receive a long-term response, while others develop resistances. Therefore, a better insight into the constitutive expression levels and their control as well as the predictive and prognostic value of PD-1/PD-L1, which are controversially discussed due to the methodological assessment, the dynamic and time-related variable expression of these molecules, is urgently required. In this review, the current knowledge of the PD-L1 and PD-1 genes, their expression in immune and tumor cells, the underlying molecular mechanisms of their regulation and their association with clinical parameters and therapy responses are summarized.
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Sung YC, Jin PR, Chu LA, Hsu FF, Wang MR, Chang CC, Chiou SJ, Qiu JT, Gao DY, Lin CC, Chen YS, Hsu YC, Wang J, Wang FN, Yu PL, Chiang AS, Wu AYT, Ko JJS, Lai CPK, Lu TT, Chen Y. Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. NATURE NANOTECHNOLOGY 2019; 14:1160-1169. [PMID: 31740794 DOI: 10.1038/s41565-019-0570-3] [Citation(s) in RCA: 290] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/03/2019] [Indexed: 05/28/2023]
Abstract
Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.
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Affiliation(s)
- Yun-Chieh Sung
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Pei-Ru Jin
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan
| | - Li-An Chu
- Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Fu-Fei Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Mei-Ren Wang
- Department of Chemistry, Chung Yuan Christian University, Taoyuan, Taiwan
| | - Chih-Chun Chang
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan
| | - Show-Jen Chiou
- Department of Applied Chemistry, National Chiayi University, Chiayi, Taiwan
| | - Jiantai Timothy Qiu
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Dong-Yu Gao
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan
| | - Chu-Chi Lin
- Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Sing Chen
- Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Chiung Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
| | - Jane Wang
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Fu-Nien Wang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Pei-Lun Yu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Ann-Shyn Chiang
- Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
| | - Anthony Yan-Tang Wu
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan
- Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
- Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan
| | - John Jun-Sheng Ko
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan
| | - Charles Pin-Kuang Lai
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan
- Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
- Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
| | - Tsai-Te Lu
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
- Department of Chemistry, Chung Yuan Christian University, Taoyuan, Taiwan.
| | - Yunching Chen
- Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
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Hashemi M, Karami S, Sarabandi S, Moazeni-Roodi A, Małecki A, Ghavami S, Wiechec E. Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies. Cancers (Basel) 2019; 11:1150. [PMID: 31405171 PMCID: PMC6721817 DOI: 10.3390/cancers11081150] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/04/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023] Open
Abstract
A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis study to identify the impact of PD-1 and PD-L1 polymorphisms on overall cancer susceptibility. The findings revealed that PD-1 rs2227981 and rs11568821 polymorphisms significantly decreased the overall cancer risk (Odds Ratio (OR) = 0.82, 95% CI = 0.68-0.99, p = 0.04, TT vs. CT+CC; OR = 0.79, 95% CI = 0.67-0.94, p = 0.006, AG vs. GG, and OR = 0.82, 95% CI = 0.70-0.96, p = 0.020, AG+AA vs. GG, respectively), while PD-1 rs7421861 polymorphism significantly increased the risk of developing cancer (OR = 1.16, 95% CI = 1.02-1.33, p = 0.03, CT vs. TT). The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41-0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50-0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60-0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63-0.96, p = 0.02) genetic models. No significant association between rs2227982, rs36084323, rs10204525, and rs2890658 polymorphisms and overall cancer risk has been found. In conclusions, the results of this meta-analysis have revealed an association between PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms and overall cancer susceptibility.
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Affiliation(s)
- Mohammad Hashemi
- Genetics of Non-communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran.
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran.
| | - Shima Karami
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran
| | - Sahel Sarabandi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran
| | - Abdolkarim Moazeni-Roodi
- Department of Clinical Biochemistry, Iranshahr University of Medical Sciences, Iranshahr 9916643535, Iran
| | - Andrzej Małecki
- Instititute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education in Katowice, 40-065 Katowice, Poland
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
- Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada.
| | - Emilia Wiechec
- Department of Clinical and Experimental Medicine, Linköping University, 58183 Linköping, Sweden.
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Shen X, Zhang L, Li J, Li Y, Wang Y, Xu ZX. Recent Findings in the Regulation of Programmed Death Ligand 1 Expression. Front Immunol 2019; 10:1337. [PMID: 31258527 PMCID: PMC6587331 DOI: 10.3389/fimmu.2019.01337] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/28/2019] [Indexed: 12/11/2022] Open
Abstract
With the recent approvals for the application of monoclonal antibodies that target the well-characterized immune checkpoints, immune therapy shows great potential against both solid and hematologic tumors. The use of these therapeutic monoclonal antibodies elicits inspiring clinical results with durable objective responses and improvements in overall survival. Agents targeting programmed cell death protein 1 (PD-1; also known as PDCD1) and its ligand (PD-L1) achieve a great success in immune checkpoints therapy. However, the majority of patients fail to respond to PD-1/PD-L1 axis inhibitors. Expression of PD-L1 on the membrane of tumor and immune cells has been shown to be associated with enhanced objective response rates to PD-1/PD-L1 inhibition. Thus, an improved understanding of how PD-L1 expression is regulated will enable us to better define its role as a predictive marker. In this review, we summarize recent findings in the regulation of PD-L1 expression.
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Affiliation(s)
- Xiangfeng Shen
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Lihong Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Jicheng Li
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yulin Li
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
| | - Zhi-Xiang Xu
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
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Zanusso C, Dreussi E, Bortolus R, Romualdi C, Gagno S, De Mattia E, Romanato L, Sartor F, Quartuccio L, Cecchin E, Toffoli G. rs4143815- PDL1, a New Potential Immunogenetic Biomarker of Biochemical Recurrence in Locally Advanced Prostate Cancer after Radiotherapy. Int J Mol Sci 2019; 20:ijms20092082. [PMID: 31035590 PMCID: PMC6539607 DOI: 10.3390/ijms20092082] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/19/2019] [Accepted: 04/25/2019] [Indexed: 12/23/2022] Open
Abstract
Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value < 0.05, q-value < 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41–0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26–1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40–0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16–0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa.
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Affiliation(s)
- Chiara Zanusso
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Eva Dreussi
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Roberto Bortolus
- Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Chiara Romualdi
- Department of Biology, University of Padova, 35122 Padova, Italy.
| | - Sara Gagno
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Elena De Mattia
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Loredana Romanato
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Franca Sartor
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Luca Quartuccio
- Rheumatology Clinic, Department of Medical and Biological Sciences, University Hospital "Santa Maria della Misericordia", 33100 Udine, Italy.
| | - Erika Cecchin
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy.
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41
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Hu L, Ma Y, Liu L, Kang L, Brito LF, Wang D, Wu H, Liu A, Wang Y, Xu Q. Detection of functional polymorphisms in the hsp70 gene and association with cold stress response in Inner-Mongolia Sanhe cattle. Cell Stress Chaperones 2019; 24:409-418. [PMID: 30838506 PMCID: PMC6439023 DOI: 10.1007/s12192-019-00973-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 01/18/2019] [Accepted: 01/22/2019] [Indexed: 10/27/2022] Open
Abstract
The genetic mechanisms underlying the cattle resilience to severe cold temperatures are still unknown. In this study, we observed that four blood biochemical parameters were significantly altered, i.e., blood adrenocorticotropic hormone (ACTH), triiodothyronine (T3), thyroxine (T4), and potassium (K+) after expose to - 32 °C for 3 h. This was observed using 105 healthy Sanhe heifers with similar weight (398.17 ± 34.06 kg) and age (19.30 ± 4.91 months). A total of 20 single nucleotide polymorphisms (SNPs) were identified in 5'-flanking region of the hsp70 gene in Sanhe cattle, while only 10 SNPs were segregating when comparing genetic variations between Sanhe cattle and 285 Chinese Holstein samples. Statistically significant associations between the genomic markers SNP-42-, SNP-105+, SNP-181+, and SNP-205+ with blood T3 and between SNP-105+ and blood T4 were observed by applying the general linear model procedure and Bonferroni t test. Furthermore, we demonstrated that the T alleles of SNP-42- and SNP-205+ in the GC box and Kozak sequence of the hsp70 gene, respectively, significantly decreased the green fluorescent proteins activity in vitro GFP reporter assays. These findings suggest that these two SNPs are causative polymorphisms involved in the regulation of hsp70 promoter activity and might contribute to the observed association between the hsp70 gene and T3 and T4 levels in Sanhe cattle. Thus, hsp70 gene is a promising candidate gene to be validated in independent cattle populations and functional studies related to cold stress resilience in cattle.
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Affiliation(s)
- Lirong Hu
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China
| | - Yao Ma
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China
| | - Lili Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction, MARA; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193 People’s Republic of China
| | - Ling Kang
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China
| | - Luiz Fernando Brito
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 USA
| | - Dongsheng Wang
- Xiertala Cattle Breeding Farm, Hailaer Farm Buro, Hailaer, Inner Mongolia 021012 People’s Republic of China
| | - Hongjun Wu
- Xiertala Cattle Breeding Farm, Hailaer Farm Buro, Hailaer, Inner Mongolia 021012 People’s Republic of China
| | - Airong Liu
- Moguai Farm, Hailaer Farm Buro, Hailaer, Inner Mongolia 022150 People’s Republic of China
| | - Yachun Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction, MARA; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193 People’s Republic of China
| | - Qing Xu
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China
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42
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Yuan W, Deng D, Jiang H, Tu C, Shang X, He H, Niu R, Dong J. Hyperresponsiveness to interferon gamma exposure as a response mechanism to anti-PD-1 therapy in microsatellite instability colorectal cancer. Cancer Immunol Immunother 2019; 68:257-268. [PMID: 30406373 PMCID: PMC11028335 DOI: 10.1007/s00262-018-2270-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 10/31/2018] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) with high-level microsatellite instability (MSI-H) tends to be associated with a better response to programmed death receptor-1 (PD-1) blockade than does microsatellite stable CRC. However, emerging evidence makes the use of programmed death ligand-1 (PD-L1) as a biomarker problematic. Here, we sought to characterize the interactions between PD-L1 expression and the response to PD-1 blockade therapy in BALB/c mice with a subcutaneous tumor challenge. We further focused on interferon gamma (IFNγ)-induced PD-L1 expression in an in vitro setting to evaluate the responsiveness to IFNγ exposure and the specific signaling of PD-1 in HCT116 and SW480 cell lines. In this study, enhanced PD-L1 expression increased survival in CT26 cells, and PD-1 blockade increased the CTL profile and apoptotic cells in mice with CRC. Our in vitro findings showed that PD-L1 expression was significantly upregulated by a low-dose IFNγ treatment, and the MSI-H cell line might exhibit hyperresponsiveness to IFNγ exposure partly through the JAK-STAT pathway. These results suggest that intrinsic PD-L1 in cooperation with extrinsic IFNγ exposure in CRC may be more responsive to anti-PD-1 therapy, mainly through the CTL profile in the tumor microenvironment.
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Affiliation(s)
- Wenli Yuan
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, 650021, People's Republic of China
| | - Deyao Deng
- Department of Clinical Laboratory, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, 650021, People's Republic of China
| | - Hongchao Jiang
- The Affiliated Children's Hospital of Kunming Medical University, Kunming, 650228, People's Republic of China
| | - Changling Tu
- Department of Cadre Medical Branch, Yunnan Cancer Hospital, Yunnan Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, People's Republic of China
| | - Xueqin Shang
- Department of Oncology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, 650021, People's Republic of China
| | - Hongchun He
- Department of General Surgery, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, 650021, People's Republic of China
| | - Ruize Niu
- Department of Laboratory Zoology, Kunming Medical University, Kunming, 650500, People's Republic of China
| | - Jian Dong
- The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, No. 519 Kun Zhou Road, Xishan District, Kunming, 650118, Yunnan, People's Republic of China.
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Fabrizio FP, Trombetta D, Rossi A, Sparaneo A, Castellana S, Muscarella LA. Gene code CD274/PD-L1: from molecular basis toward cancer immunotherapy. Ther Adv Med Oncol 2018; 10:1758835918815598. [PMID: 30574211 PMCID: PMC6299305 DOI: 10.1177/1758835918815598] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 10/31/2018] [Indexed: 12/18/2022] Open
Abstract
The programmed death 1 receptor (PD-1) and its ligand (PD-L1) are key molecules of immune checkpoint mechanisms in cancer and actually represent one of the main targets of immunotherapy. The predictive and prognostic values of PD-L1 expression alone in cancer patients is currently under debate due to the methodological assessment of PD-L1 expression and its temporal variations. Better detailed studies about the molecular basis of immunotherapy biomarkers are necessary. Here we summarize the current knowledge of PD-L1 gene modifications at genetic and epigenetic levels in different tumors, thus highlighting their reported correlation with cellular processes and potential impact on patient outcomes.
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Affiliation(s)
- Federico Pio Fabrizio
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Domenico Trombetta
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Antonio Rossi
- Department of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Angelo Sparaneo
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Stefano Castellana
- Bioinformatic Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Lucia Anna Muscarella
- Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
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Zou J, Wu D, Li T, Wang X, Liu Y, Tan S. Association of PD-L1 gene rs4143815 C>G polymorphism and human cancer susceptibility: A systematic review and meta-analysis. Pathol Res Pract 2018; 215:229-234. [PMID: 30552042 DOI: 10.1016/j.prp.2018.12.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/17/2018] [Accepted: 12/05/2018] [Indexed: 12/31/2022]
Abstract
Programmed death ligand 1(PD-L1) mediated immune escape play important roles in the development of cancer. The gene polymorphism of PD-L1, in particular rs4143815 C > G, has been associated with the cancer risks, but with conflicting results. Therefore, this meta-analysis was aimed to assess the association between rs4143815 C > G and cancer susceptibility. A systematic literature search was performed to select the studies and the pooled odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of association. Eleven eligible studies containing 3711 cases and 3704 controls were enrolled in the meta-analysis. The results suggested that there is a strong association between rs4143815 C > G and the cancer risks (G vs. C: OR = 1.386, 95% CI: 1.132-1.696, p = 0.002; GG vs. CG + CC: OR = 1.843 95% CI: 1.300-2.613, p = 0.002; GG + CG vs. CC: OR = 1.280, 95% CI: 1.040-1.576, p = 0.020). Subgroup analysis based on cancer type suggested that PD-L1 rs4143815 C > G might increase the susceptibility to gastric cancer (G vs. C: OR = 1.842, 95% CI: 1.403-2.418, p < 0.001) and bladder cancer (G vs. C: OR = 2.015, 95% CI: 1.556-2.608, p < 0.001), and genotype GG carriers of PD-L1 rs4143815 C > G might have higher risks of HCC (GG vs. CG + CC: OR = 2.226 95% CI: 1.562-3.172, p < 0.001). PD-L1 rs4143815 C > G might confer an increased cancer risk, indicating this SNP may contribute to the pathogenesis of cancer and might be used as a potential biomarker to predict the susceptibility to cancer.
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Affiliation(s)
- Ju Zou
- Department of Parasitology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Daichao Wu
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China.
| | - Tao Li
- Grade 2015 of Clinical Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Xianwen Wang
- Grade 2015 of Clinical Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Yan Liu
- Department of Parasitology, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Sijie Tan
- Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China.
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45
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Li H, Xia JQ, Zhu FS, Xi ZH, Pan CY, Gu LM, Tian YZ. LPS promotes the expression of PD-L1 in gastric cancer cells through NF-κB activation. J Cell Biochem 2018; 119:9997-10004. [PMID: 30145830 DOI: 10.1002/jcb.27329] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 06/26/2018] [Indexed: 12/15/2022]
Abstract
Gastric cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. Gastric infections, such as helicobacter pylori, can induce the occurrence of gastric cancers. However, the role of gastric infection in gastric cancer development is unclear. Programmed death-ligand 1 (PD-L1, B7-H1) is a member of the B7 family of cell surface ligands, which binds the PD-1 transmembrane receptor and inhibits T-cell activation within cancer tissues. It has been reported that the expression of PD-L1 is inversely related to the prognosis of patients with gastric cancers. Therefore, the regulation of PD-L1 expression in gastric cancers needs to be studied. In the current study, we explored the possible effects of lipopolysaccharide (LPS) on PD-L1 expression in gastric cancer cells. We observed that LPS stimulation could markedly increase PD-L1 expression in gastric cancer cells. Furthermore, we found that nuclear factor-κB (NF-κB) activation was involved in PD-L1 expression in gastric cancer cells exposed to LPS stimulation through p65-binding to the PD-L1 promoter. Taken together, these data indicate that gastric infection might promote the development of gastric cancers thought the LPS-NF-κB-PD-L1 axis.
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Affiliation(s)
- Hui Li
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jun-Quan Xia
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Fang-Shi Zhu
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhao-Hong Xi
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Cheng-Yu Pan
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Li-Mei Gu
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yao-Zhou Tian
- Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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46
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Xie Q, Chen Z, Xia L, Zhao Q, Yu H, Yang Z. Correlations of PD-L1 gene polymorphisms with susceptibility and prognosis in hepatocellular carcinoma in a Chinese Han population. Gene 2018; 674:188-194. [PMID: 29940275 DOI: 10.1016/j.gene.2018.06.069] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 06/11/2018] [Accepted: 06/20/2018] [Indexed: 12/21/2022]
Abstract
AIMS This study was performed to investigate the effect of PD-L1 polymorphisms on the susceptibility and prognosis of hepatocellular carcinoma (HCC) in a Chinese Han population. METHODS Four single nucleotide polymorphisms (SNPs) of the PD-L1 gene, including rs2297136 (C > T), rs4143815 (C > G), rs2890658 (A > C) and rs17718883 (C > G) were examined in 225 HCC patients and 200 healthy controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS Data revealed that the rs2297136 (C > T) SNP TT (p = 0.03) and rs4143815 (C > G) SNP GG genotypes (p < 0.001) were associated with significantly increased risks of HCC. No association was found between rs2890658 (A > C) SNP and HCC risk and this risk was significantly decreased in individuals with the rs17718883 SNP CG + GG genotype (p < 0.001). The rs2297136 (C > T) SNP CC + CT genotypes, the rs4143815 (C > G) CC genotype and the rs2890658 (A > C) AA genotype were associated with increased overall survival compared to their counterpart allelic genotypes (p < 0.001). The rs2890658 (A > C) SNP had no impact on the risk and prognosis of HCC (p > 0.05). CONCLUSIONS Our results indicated that three functional polymorphisms (rs2297136, rs4143815 and rs17718883) of the PD-L1 gene were associated with HCC risk and prognosis, suggesting that genetic variants of PD-L1 polymorphisms might be a possible prognostic marker for the prediction of HCC risk and development. Validation by a larger prospective study from a more diverse ethnic population is needed to confirm these findings.
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Affiliation(s)
- Qigui Xie
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
| | - Zhanlei Chen
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
| | - Liang Xia
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
| | - Qiufeng Zhao
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, PR China
| | - Haitao Yu
- Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| | - Zhuying Yang
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, PR China.
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47
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Tan D, Sheng L, Yi QH. Correlation of PD-1/PD-L1 polymorphisms and expressions with clinicopathologic features and prognosis of ovarian cancer. Cancer Biomark 2018; 21:287-297. [PMID: 29171986 DOI: 10.3233/cbm-170357] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Dan Tan
- Department of Obstetrics and Gynecology, The First People’s Hospital of Jingzhou City, Jingzhou 434000, Hubei, China
| | - Li Sheng
- Department of Ultrasound, The First People’s Hospital of Jingzhou City, Jingzhou 434000, Hubei, China
| | - Qing-Hua Yi
- Department of Obstetrics and Gynecology, The First People’s Hospital of Jingzhou City, Jingzhou 434000, Hubei, China
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48
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Qian C, Guo H, Chen X, Shi A, Li S, Wang X, Pan J, Fang C. Association of PD-1 and PD-L1 Genetic Polymorphyisms with Type 1 Diabetes Susceptibility. J Diabetes Res 2018; 2018:1614683. [PMID: 30534571 PMCID: PMC6252202 DOI: 10.1155/2018/1614683] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 10/15/2018] [Indexed: 12/31/2022] Open
Abstract
AIMS The programmed death- (PD-) 1/PD-1 ligand (PD-L) pathway plays an important role in regulating T cell activation and maintaining peripheral tolerance. Accumulated studies showed that PD-1/PD-L1 pathway was involved in the development of type 1 diabetes (T1DM). Since the genetic background of type 1 diabetes differs greatly among the different population, we aim to investigate the association of genetic polymorphisms in PD-1 and PD-L1 with T1DM susceptibility in Chinese population. METHODS In total, 166 T1DM patients and 100 healthy controls were enrolled into the study. Genomic DNA was extracted from 4 mL peripheral blood samples collected from each subject. Genotyping of 8 selected SNPs of PD-1 and PD-L1 was carried out by the pyrosequencing PSQ 24 System using PyroMark Gold reagents (QIAGEN). RESULTS SNP rs4143815 in PD-L1 was significantly associated with T1DM. People carrying the C allele of rs4143815 suffering less risk of T1DM and T1DM patients with G/G genotype showed higher levels of autoantibody (AAB) positive incidence compared with C allele carriers. No significant associations were found in other SNPs. CONCLUSIONS Our results indicate that rs4143815 of PD-L1 is significantly associated with T1DM and may serve as a new biomarker to predict the T1DM susceptibility.
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Affiliation(s)
- Chenyue Qian
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Heming Guo
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Xiaohong Chen
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Aiming Shi
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Sicheng Li
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Xin Wang
- Department of Endocrinology, Jiangsu Province Hospital of TCM, 155 Hanzhonglu, Jiangsu Nanjing 210029, China
| | - Jie Pan
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Chen Fang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
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49
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Cubillos-Zapata C, Avendaño-Ortiz J, Hernandez-Jimenez E, Toledano V, Casas-Martin J, Varela-Serrano A, Torres M, Almendros I, Casitas R, Fernández-Navarro I, Garcia-Sanchez A, Aguirre LA, Farre R, López-Collazo E, García-Rio F. Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea. Eur Respir J 2017; 50:50/4/1700833. [PMID: 29051270 DOI: 10.1183/13993003.00833-2017] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 07/23/2017] [Indexed: 12/16/2022]
Abstract
Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.
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Affiliation(s)
- Carolina Cubillos-Zapata
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Jose Avendaño-Ortiz
- The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Enrique Hernandez-Jimenez
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Victor Toledano
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Jose Casas-Martin
- The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | | | - Marta Torres
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,Sleep Laboratory, Pneumology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Isaac Almendros
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,Biophysics and Bioengineering Unit, Faculty of Medicine, University of Barcelona-IDIBAPS, Barcelona, Spain
| | - Raquel Casitas
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Isabel Fernández-Navarro
- Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Aldara Garcia-Sanchez
- Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Luis A Aguirre
- The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, Madrid, Spain
| | - Ramón Farre
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,Biophysics and Bioengineering Unit, Faculty of Medicine, University of Barcelona-IDIBAPS, Barcelona, Spain
| | - Eduardo López-Collazo
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.,The Innate Immune Response Group, La Paz University Hospital, IdiPAZ, Madrid, Spain.,Joint principal investigators
| | - Francisco García-Rio
- Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain .,Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain.,Dept of Medicine, Autonomous University of Madrid, Madrid, Spain.,Joint principal investigators
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50
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Wang W, Liao P, He Y. A gene polymorphism in PD-L1 promoter region is not associated with PD-L1 expression and patients' survival in gastric cancer. Cancer Immunol Immunother 2017; 66:1379-1381. [PMID: 28540431 PMCID: PMC11028970 DOI: 10.1007/s00262-017-2017-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 05/10/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Weili Wang
- Department of Clinical Pharmacology, Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiangya Road 110, Changsha, 410000, Hunan, China
| | - Ping Liao
- Department of Clinical Pharmacology, Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiangya Road 110, Changsha, 410000, Hunan, China
| | - Yijing He
- Department of Clinical Pharmacology, Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiangya Road 110, Changsha, 410000, Hunan, China.
- Department of Dermatology, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Xiangya Road 110, Changsha, 410000, Hunan, China.
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