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Zhang XJ, Yu Y, Zhao HP, Guo L, Dai K, Lv J. Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer. World J Gastroenterol 2024; 30:2195-2208. [PMID: 38690024 PMCID: PMC11056912 DOI: 10.3748/wjg.v30.i16.2195] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/05/2024] [Accepted: 04/10/2024] [Indexed: 04/26/2024] Open
Abstract
As a highly invasive malignancy, esophageal cancer (EC) is a global health issue, and was the eighth most prevalent cancer and the sixth leading cause of cancer-related death worldwide in 2020. Due to its highly immunogenic nature, emer-ging immunotherapy approaches, such as immune checkpoint blockade, have demonstrated promising efficacy in treating EC; however, certain limitations and challenges still exist. In addition, tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment (TIME); thus, understanding the TIME is urgent and crucial, especially given the im-portance of an immunosuppressive microenvironment in tumor progression. The aim of this review was to better elucidate the mechanisms of the suppressive TIME, including cell infiltration, immune cell subsets, cytokines and signaling pathways in the tumor microenvironment of EC patients, as well as the downregulated expression of major histocompatibility complex molecules in tumor cells, to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies. Therefore, personalized treatments could be developed to maximize the advantages of immunotherapy.
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Affiliation(s)
- Xiao-Jun Zhang
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Kun Dai
- Department of Clinical Laboratory, Yanliang Railway Hospital of Xi’an, Xi’an 710089, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Tang W, Wang J, Dai T, Qiu H, Liu C, Chen S, Hu Z. Association of leptin receptor polymorphisms with susceptibility of non-small cell lung cancer: Evidence from 2249 subjects. Cancer Med 2024; 13:e7178. [PMID: 38659416 PMCID: PMC11043686 DOI: 10.1002/cam4.7178] [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: 11/12/2023] [Revised: 03/20/2024] [Accepted: 03/28/2024] [Indexed: 04/26/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) is increasing dramatically. It is believed that energy metabolism-related genes could play an important role in etiology of NSCLC. In this study, we sought to assess the correlation between three LEPR single nucleotide polymorphisms (rs1137101, rs1137100 and rs6588147) with NSCLS susceptibility. In total, 1193 NSCLC cases and 1056 controls were included. SNPscan™ genotyping method was used to analyze the genotypes of LEPR polymorphisms. Compared to rs6588147 GG in LEPR gene, this study identified a protective role of LEPR rs6588147 GA and GA/AA for the occurrence of NSCLC (GA vs. GG [p = 0.021] and GA/AA vs. GG [p = 0.030]). As well, we found that a protective role of LEPR rs6588147 for the occurrence of non-SCC subgroup (p < 0.05). By logistic regression analysis, we found that the rs6588147 A allele related genotypes might play a protective role for the occurrence of NSCLC in drinking, BMI ≥24 kg/m2, smoking and male subgroups. We also found that the rs1137101 A allele related genotypes played a protective role for the occurrence of NSCLC in male, younger participants (under 59 years) and overweight/obesity (BMI ≥24 kg/m2) subgroups. We found that LEPR Ars1037100Ars1037101Ars6588147 haplotype might play a protective role for the occurrence of NSCLC (p = 0.013). In addition, our findings indicated that LEPR rs1137100 G>A SNP might increase the risk of lymph node metastases (p = 0.038). This study highlights that LEPR rs6588147, rs1137101 genotypes and LEPR Ars1037100Ars1037101Ars6588147 haplotype are correlated with the occurrence of NSCLC. LEPR rs1137100 G>A SNP increases the risk of lymph node metastases.
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Affiliation(s)
- Weifeng Tang
- Departments of Esophageal Surgery and Thoracic SurgeryNanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolNanjing210008Jiangsu ProvinceChina
| | - Jian Wang
- Department of Cardiothoracic SurgeryAffiliated Yixing People's Hospital of Jiangsu UniversityYixingJiangsu ProvinceChina
| | - Ting Dai
- Department of PharmacyAffiliated Yixing People's Hospital of Jiangsu UniversityYixingJiangsu ProvinceChina
| | - Hao Qiu
- Department of Laboratory Medicine, School of MedicineJiangsu UniversityZhenjiangJiangsu ProvinceChina
| | - Chao Liu
- Department of Cardiothoracic SurgeryAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsu ProvinceChina
| | - Shuchen Chen
- Department of Thoracic SurgeryFujian Medical University Union HospitalFuzhouFujian ProvinceChina
| | - Zhendong Hu
- Departments of Esophageal Surgery and Thoracic SurgeryNanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolNanjing210008Jiangsu ProvinceChina
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Andrzejczak A, Karabon L. BTLA biology in cancer: from bench discoveries to clinical potentials. Biomark Res 2024; 12:8. [PMID: 38233898 PMCID: PMC10795259 DOI: 10.1186/s40364-024-00556-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 12/31/2023] [Indexed: 01/19/2024] Open
Abstract
Immune checkpoints play a critical role in maintaining the delicate balance of immune activation in order to prevent potential harm caused by excessive activation, autoimmunity, or tissue damage. B and T lymphocyte attenuator (BTLA) is one of crucial checkpoint, regulating stimulatory and inhibitory signals in immune responses. Its interaction with the herpes virus entry mediator (HVEM) plays an essential role in negatively regulating immune responses, thereby preserving immune homeostasis. In cancer, abnormal cells evade immune surveillance by exploiting checkpoints like BTLA. Upregulated BTLA expression is linked to impaired anti-tumor immunity and unfavorable disease outcomes. In preclinical studies, BTLA-targeted therapies have shown improved treatment outcomes and enhanced antitumor immunity. This review aims to provide an in-depth understanding of BTLA's biology, its role in various cancers, and its potential as a prognostic factor. Additionally, it explores the latest research on BTLA blockade in cancer immunotherapy, offering hope for more effective cancer treatments.
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Affiliation(s)
- Anna Andrzejczak
- Laboratory of Genetics and Epigenetics of Human Diseases, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Lidia Karabon
- Laboratory of Genetics and Epigenetics of Human Diseases, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
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Gao X, Gao Y, Pan S, Yang L. Clinical significance of BTLA gene expression and rs1982809 polymorphism in pan-cancer. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2023; 43:1065-1076. [PMID: 38117093 DOI: 10.1080/15257770.2023.2296615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 09/25/2023] [Accepted: 12/13/2023] [Indexed: 12/21/2023]
Abstract
The association between the B and T lymphocyte attenuator (BTLA) gene rs1982809 polymorphism and cancer susceptibility has been reported, but these findings are inconsistent. In addition to clarifying the relationship between the rs1982809 polymorphism and cancer susceptibility, the current study also explored the clinical significance of BTLA gene expression. The GSCA tool and Stata software were used to explore the association between BTLA gene expression and tumor stage, immune infiltration, survival prognosis, and drug sensitivity for pan-cancer, and the association of BTLA gene rs1982809 polymorphism with cancer susceptibility, respectively. BTLA gene expression was associated not only with the pathologic stages of thyroid carcinoma, skin cutaneous melanoma, and kidney renal clear cell carcinoma, but also with immune infiltration in 33 types of cancers. In addition, BTLA gene expression was linked to survival prognosis in 8 types of cancers and the sensitivity of 255 drugs such as 5-Fluorouracil, docetaxel, and methotrexate. A meta-analysis of 7 relevant studies with 4002 cancer patients and 5278 healthy controls showed that the BTLA gene rs1982809 polymorphism was unrelated to cancer susceptibility under all genetic models. However, a country-based stratification analysis suggested that the rs1982809 polymorphism could reduce cancer susceptibility in Polish and Tunisian populations. In conclusion, BTLA is expected to serve as a prognostic marker and therapeutic target for certain cancers, and the rs1982809 polymorphism is expected to serve as a cancer susceptibility marker in Polish and Tunisian populations.
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Affiliation(s)
- Xueren Gao
- School of Pharmacy, Yancheng Teachers' University, Jiangsu, China
| | - Yichang Gao
- School of Pharmacy, Nanjing University of Chinese Medicine, Jiangsu, China
| | - Shiyu Pan
- School of Pharmacy, Yancheng Teachers' University, Jiangsu, China
| | - Lin Yang
- School of Pharmacy, Yancheng Teachers' University, Jiangsu, China
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Mohamed AH, Obeid RA, Fadhil AA, Amir AA, Adhab ZH, Jabouri EA, Ahmad I, Alshahrani MY. BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression. Cytokine 2023; 172:156412. [PMID: 39492110 DOI: 10.1016/j.cyto.2023.156412] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 10/22/2023] [Accepted: 10/25/2023] [Indexed: 11/05/2024]
Abstract
Immunotherapy has emerged as a revolutionary cancer treatment, particularly with the introduction of immune checkpoint inhibitors (ICIs). ICIs target specific proteins that restrain the immune system from attacking cancer cells. Prominent examples of checkpoint proteins that ICIs block include PD-1, PD-L1, and CTLA-4. The success of PD-1/L1 and CTLA-4 blockade has prompted further research on other inhibitory mechanisms that could aid in the treatment of cancer. One such mechanism is the BTLA/HVEM checkpoint, which regulates immune responses in a similar manner to CTLA-4 and PD-1. BTLA, a member of the Ig superfamily, binds to HVEM, a member of the TNF receptor superfamily. While BTLA is essential for maintaining immunological self-tolerance and preventing autoimmune diseases, overexpression of BTLA and HVEM has been observed in various malignancies such as lung, ovarian, glioblastoma, gastric cancer, and non-Hodgkin's lymphoma. The function of the BTLA/HVEM checkpoint in various malignancies has been extensively studied, revealing its significant role in immunotherapy for cancer. This review study aims to explain the BTLA/HVEM checkpoint and its functions in different types of cancers. In conclusion, the development of new immunotherapies such as ICIs has revolutionized cancer treatment. The discovery of the BTLA/HVEM checkpoint and its role in various malignancies provides opportunities for advancing cancer treatment through immunotherapy.
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Affiliation(s)
- Asma'a H Mohamed
- Intelligent Medical Systems Department, Al-Mustaqbal University College, 51001 Hilla, Babylon, Iraq
| | - Ruaa Ali Obeid
- College of Pharmacy, Department of Pharmaceutics, University of Al-Ameed, Iraq
| | | | - Ahmed Ali Amir
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Zainab H Adhab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Enaam Anad Jabouri
- Department of Medical Laboratory Technics, AlNoor University College, Nineveh, Iraq
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
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Andrzejczak A, Partyka A, Wiśniewski A, Porębska I, Pawełczyk K, Ptaszkowski K, Kuśnierczyk P, Jasek M, Karabon L. The association of BTLA gene polymorphisms with non-small lung cancer risk in smokers and never-smokers. Front Immunol 2023; 13:1006639. [PMID: 36741370 PMCID: PMC9893504 DOI: 10.3389/fimmu.2022.1006639] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/19/2022] [Indexed: 01/20/2023] Open
Abstract
Introduction Lung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response. A growing body of evidence highlights the important role of BTLA in cancer. In our previous studies, we showed a significant association between BTLA gene variants and susceptibility to chronic lymphoblastic leukemia and renal cell carcinoma in the Polish population. The present study aimed to analyze the impact of BTLA polymorphic variants on the susceptibility to NSCLC and NSCLC patients' overall survival (OS). Methods Using TaqMan probes we genotyped seven BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs9288953, rs1844089, rs11921669 and rs2633582 with the use of ViiA 7 Real-Time PCR System. Results We found that rs1982809 within BTLA is associated with NSCLC risk, where carriers of rs1982809G allele (AG+GG genotypes) were more frequent in patients compared to controls. In subgroup analyses, we also noticed that rs1982809G carriers are significantly overrepresented in never-smokers, but not in smokers compared to controls. Additionally, the global distribution of the haplotypes differed between the never-smokers and smokers, where haplotypes A G G C A, C G A C G, and C G A T G were more frequent in never-smoking patients. Furthermore, the presence rs1982809G (AG+GG genotypes) allele as well as the presence of rs9288953T allele (CT+TT genotypes) increased NSCLC risk in females' patients. After stratification by histological type, we noticed that rs1982809G and rs2705511C carriers were more frequent among adenocarcinoma patients. Moreover, rs1982809G and rs2705511C correlated with the more advanced stages of NSCLC (stage II and III), but not with stage IV. Furthermore, we showed that rs2705511 and rs1982809 significantly modified OS, while rs9288952 tend to be associated with patients' survival. Conclusion Our results indicate that BTLA polymorphic variants may be considered low penetrating risk factors for NSCLC especially in never-smokers, and in females, and are associated with OS of NSCLC patients.
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Affiliation(s)
- Anna Andrzejczak
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland,*Correspondence: Anna Andrzejczak, ; Lidia Karabon,
| | - Anna Partyka
- Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Andrzej Wiśniewski
- Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Irena Porębska
- Department of Pulmonology and Lung Oncology, Wrocław Medical University, Wrocław, Poland
| | - Konrad Pawełczyk
- Departament of Thoracic Surgery, Lower Silesian Centre of Oncology, Pulmonology and Haematology, Wrocław, Poland
| | - Kuba Ptaszkowski
- Department of Clinical Biomechanics and Physiotherapy in Motor System Disorders, Wrocław Medical University, Wrocław, Poland
| | - Piotr Kuśnierczyk
- Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - 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, Wrocław, Poland
| | - Lidia Karabon
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland,*Correspondence: Anna Andrzejczak, ; Lidia Karabon,
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Chen J, Wang J, Liu R, Xiong H, Liu Y, Zha M, Li Q, Liu X, Shang M, Li Y. The correlation of BTLA rs1982809 polymorphism with cancer susceptibility: A meta-analysis of 8634 participators. Medicine (Baltimore) 2022; 101:e29610. [PMID: 35945755 PMCID: PMC9351928 DOI: 10.1097/md.0000000000029610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The connection between B and T lymphocyte attenuator rs1982809 polymorphism and cancer risk has been investigated by several studies and yielded different results. Therefore, we adopted the meta-analysis method to assess the association of rs1982809 polymorphism with the susceptibility of cancers synthetically. METHODS Eligible publications were gathered by retrieving PubMed, Web of Science, Embase, Wan Fang, and China National Knowledge Infrastructure. We utilized odds ratio (OR) and 95% confidence intervals (95% CI) to assess correlation intensity and performed subgroup analyses, sensitivity analyses, and publication bias assessments. RESULTS Six researches that encompassed 3678 cases and 4866 controls were incorporated into our meta-analysis. The rs1982809 polymorphism was proved to be connected with cancer risk by the meta-analysis in the additive model (G vs A: OR = 1.11, 95% CI = 1.04-1.19, Pheterogeneity= .096). Subgroup analyses revealed that this SNP is regarded as a susceptible factor for cancers in the dominant, heterozygous, and additive model (AG + GG vs AA: OR = 1.46, 95% CI = 1.19-1.80, Pheterogeneity= .592; AG vs AA: OR = 1.47, 95% CI = 1.19-1.82, Pheterogeneity= .536; G vs A: OR = 1.32, 95% CI = 1.12-1.55, Pheterogeneity= .745) in Caucasians; And this SNP may increase the susceptibility to lung cancer (GG vs AG+AA: OR = 1.20, CI = 1.01-1.44, Pheterogeneity= .854; G vs A: OR = 1.17, CI = 1.02-1.33, Pheterogeneity= .232). CONCLUSION The paper concludes that B and T lymphocyte attenuator rs1982809 polymorphism may contribute to cancers, especially in Caucasians, and it may associate with lung cancer.
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Affiliation(s)
- Jian Chen
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Jun Wang
- General Surgery Department, Jing’an people’s Hospital, Yichun, Jiangxi
| | - Ruihao Liu
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Haiwei Xiong
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Yingying Liu
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Mingzhi Zha
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Qiang Li
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Xuan Liu
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Mingjun Shang
- Anesthesiology Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Yingliang Li
- General Surgery Department, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
- * Correspondence: Yingliang Li, General Surgery Department, First Affiliated Hospital of Nanchang University, No 17, YongWaiZheng Street, DongHu District, Nanchang 330006, Jiangxi, China (e-mail: )
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Lin J, Chen H, Huang Y, Tang W, Zhang S, Chen Y. Lack of Association Between PDCD-1 Polymorphisms and Colorectal Cancer Risk: A Case-Control Study. Immunol Invest 2022; 51:1867-1882. [PMID: 35499255 DOI: 10.1080/08820139.2022.2069504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Functional variants of immune-related genes may be implicated in the occurrence of colorectal cancer (CRC). In this study, Programmed cell death (PDCD)-1.6 (rs10204525 T/C), PDCD-1.7 (rs7421861 A/G), and PDCD-1.9 (rs2227982 A/G) loci were selected to explore gene expression and the potential susceptibility to the development of CRC. Here, 1,003 CRC patients and 1,303 controls were included and three PDCD-1 tagging loci were selected and analyzed by using SNPscan genotyping assays. SHESIS software was harnessed to obtain the haplotypes of the PDCD-1 gene. We found that the genotype and allele distribution of PDCD-1 tagging loci did not significantly affect the risk of CRC. Adjustment for body mass index, age, smoking, alcohol using and sex also found that PDCD-1 tagging loci did not influence the occurrence of CRC. In conclusion, this study suggests that the PDCD-1 tagging loci (rs10204525, rs7421861, and rs2227982) are not correlated with CRC susceptibility.
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Affiliation(s)
- Jing Lin
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian, China.,Center, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalCancer Bio-Immunotherapy, Fuzhou, Fujian, China
| | - Hanshen Chen
- Department of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yufang Huang
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian, China.,Center, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalCancer Bio-Immunotherapy, Fuzhou, Fujian, China
| | - Weifeng Tang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Sheng Zhang
- Department of General Surgery, Changzhou Third People's Hospital, Changzhou, Jiangsu, China
| | - Yu Chen
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian, China.,Center, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalCancer Bio-Immunotherapy, Fuzhou, Fujian, China.,College of Chemistry, Fuzhou University, Fuzhou, China
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Tupikowski K, Partyka A, Pawlak EA, Ptaszkowski K, Zdrojowy R, Frydecka I, Hałoń A, Karabon L. Variation in the gene encoding the co-inhibitory molecule BTLA is associated with survival in patients treated for clear cell renal carcinoma - results of a prospective cohort study. Arch Med Sci 2021; 19:1454-1462. [PMID: 37732048 PMCID: PMC10507760 DOI: 10.5114/aoms/142407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 09/19/2021] [Indexed: 09/22/2023] Open
Abstract
Introduction The successful introduction of immune checkpoint blockade approaches to renal-cell carcinoma (RCC) treatment indicates the importance of molecules regulating the T cell response to RCC risk and progression. Material and methods In this study, we evaluate the association of variations in the CTLA-4, BTLA and CD28 genes with overall survival (OS) of RCC patients and specifically clear cell RCC (ccRCC) patients. The following single nucleotide polymorphisms (SNPs) previously genotyped using the RFLP method or TaqMan SNP Genotyping Assays were analyzed: CTLA-4 gene: c.49A>G (rs231775), g.319C>T (rs5742909), g.*6230G>A (CT60; rs3087243), g.*10223G>T (Jo31; rs11571302); CD28 gene: c.17+3T>C (rs3116496), c.-1042G>A (rs3181098); BTLA gene: rs2705511, rs1982809, rs9288952, rs9288953, rs2705535 and rs1844089. Results During long term observation (6.5 years) we discovered that possessing the A allele at BTLA rs1844089 SNP, together with advanced disease (stage ≥ 3, tumor grade > 3, tumor diameter ≥ 70 mm), is an independent risk factor of death which increases the hazard ratio (HR) of death by more than two-fold (HR = 2.21, 95% CI: 1.28-3.83). Furthermore, the OS of patients bearing this allele is 6 months shorter than for homozygous (GG) patients (42.5 vs. 48.2 months). Conclusions Our results indicate for the first time that genetic variation within the gene encoding BTLA is significantly associated with overall survival in clear cell renal cell carcinoma patients.
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Affiliation(s)
| | - Anna Partyka
- Department of Experimental Therapy, L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland
| | - Edyta A. Pawlak
- Department of Experimental Therapy, L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland
| | - Kuba Ptaszkowski
- Department of Clinical Biomechanics and Physiotherapy in Motor System Disorders, Wroclaw Medical University, Wroclaw, Poland
| | - Romuald Zdrojowy
- Department of Urology and Oncological Urology, Wroclaw Medical University, Wroclaw, Poland
| | - Irena Frydecka
- Department of Experimental Therapy, L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland
| | - Agnieszka Hałoń
- Department of Pathomorphology, Wroclaw Comprehensive Cancer Center, Wroclaw, Poland
- Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, Wroclaw, Poland
| | - Lidia Karabon
- Department of Experimental Therapy, L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland
- Department of Urology and Oncological Urology, Wroclaw Medical University, Wroclaw, Poland
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Ning Z, Liu K, Xiong H. Roles of BTLA in Immunity and Immune Disorders. Front Immunol 2021; 12:654960. [PMID: 33859648 PMCID: PMC8043046 DOI: 10.3389/fimmu.2021.654960] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
B and T lymphocyte attenuator (BTLA) is one of the most important cosignaling molecules. It belongs to the CD28 superfamily and is similar to programmed cell death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) in terms of its structure and function. BTLA can be detected in most lymphocytes and induces immunosuppression by inhibiting B and T cell activation and proliferation. The BTLA ligand, herpesvirus entry mediator (HVEM), does not belong to the classic B7 family. Instead, it is a member of the tumor necrosis factor receptor (TNFR) superfamily. The association of BTLA with HVEM directly bridges the CD28 and TNFR families and mediates broad and powerful immune effects. Recently, a large number of studies have found that BTLA participates in numerous physiopathological processes, such as tumor, inflammatory diseases, autoimmune diseases, infectious diseases, and transplantation rejection. Therefore, the present work aimed to review the existing knowledge about BTLA in immunity and summarize the diverse functions of BTLA in various immune disorders.
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Affiliation(s)
- Zhaochen Ning
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China.,Jining Key Laboratory of Immunology, Jining Medical University, Jining, China
| | - Keyan Liu
- Department of Public Health, Jining Medical University, Jining, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China.,Jining Key Laboratory of Immunology, Jining Medical University, Jining, China
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Association of BTLA Polymorphisms with Susceptibility to Non-Small-Cell Lung Cancer in the Chinese Population. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9121824. [PMID: 33564688 PMCID: PMC7867466 DOI: 10.1155/2021/9121824] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/14/2020] [Accepted: 01/13/2021] [Indexed: 12/24/2022]
Abstract
Studies have reported that B- and T-lymphocyte attenuator (BTLA) polymorphisms may be associated with the risk to different cancers. However, the correlation between those variations and non-small-cell lung cancer (NSCLC) is still unclear. A total of 1,003 NSCLC patients and 901 noncancer controls were recruited in the study, to confirm the association of variations in BTLA gene with the risk of NSCLC. The SNPscan™ genotyping assay was used to obtain the genotypes of the four BTLA polymorphisms (BTLA rs1982809 G>A, rs16859629 T>C, rs2171513 G>A, and rs3112270 A>G). It was found that BTLA rs1982809 polymorphism reduced the risk of NSCLC (GA vs. GG: adjusted odds ratio (OR) = 0.81, 95%confidence interval (CI) = 0.66‐0.99, and P = 0.043). However, the BTLA rs16859629, rs2171513, and rs3112270 polymorphisms showed no significant association between NSCLC patients and controls in overall comparison. In subgroup analyses, we found that BTLA rs1982809 polymorphism reduced the risk of NSCLC (nonsquamous cell carcinoma: GA vs. GG: adjusted OR = 0.79, 95%CI = 0.64‐0.97, and P = 0.026; AA/GA vs. GG: adjusted OR = 0.81, 95%CI = 0.66‐0.99, and P = 0.037; ≥59 years: GA vs. GG: P = 0.036; never alcohol consumption: GA vs. GG: P = 0.013; GA/AA vs. GG: P = 0.016; body mass index (BMI) ≥ 24 kg/m2: GA vs. GG: P = 0.030; GA/AA vs. GG: P = 0.041). The BTLA rs16859629 polymorphism increased the risk of the development of squamous cell carcinoma (CC vs. TT: adjusted OR = 9.85, 95%CI = 1.37‐71.03, and P = 0.023; CC vs. TT/TC: adjusted OR = 9.55, 95%CI = 1.32‐68.66, and P = 0.025). Taken together, the findings of the present suggest that BTLA rs1982809 and rs16859629 polymorphisms may influence the susceptibility to NSCLC in the Chinese population.
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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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Zhao RP, Li Z, Li C, Xu K, Zhen LL, Song W, Shi JH. A Genetic Variant of the BTLA Gene is Related to Increased Risk and Clinical Manifestations of Breast Cancer in Chinese Women. Clin Breast Cancer 2020; 21:e512-e517. [PMID: 33642196 DOI: 10.1016/j.clbc.2020.12.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/07/2020] [Accepted: 12/22/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND B and T lymphocyte attenuator (BTLA), an immunoinhibitory receptor, is shown to suppress the lymphocyte activation. Several studies addressed the relationship between the BTLA rs1982809 polymorphism and the risk of cancer. PATIENTS AND METHODS To identify the effects of this polymorphism on the risk of breast cancer (BC), this study examined Chinese women from China, Jiangsu Province. This study involved 324 patients with BC and 412 controls. RESULTS We observed that the BTLA rs1982809 polymorphism elevated the risk of BC. A similar finding was also shown in the subgroups of premenopausal women and those aged < 55 years old. In addition, this polymorphism was correlated with the estrogen receptor status, C-erbB-2 status, Ki-67 status, TNM stage, and tumor size of patients with BC. CONCLUSIONS Collectively, the BTLA rs1982809 polymorphism shows a significant association with elevated risk and clinical features of BC in Chinese women. Further studies involving other races are urgently needed to replicate these findings.
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Affiliation(s)
- Rui-Peng Zhao
- Department of Thyroid and Breast Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Zhi Li
- Department of Thyroid and Breast Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Chang Li
- Department of Clinical Laboratory, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Kang Xu
- Department of Clinical Laboratory, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Lin-Lin Zhen
- Department of Thyroid and Breast Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Wei Song
- Department of Thyroid and Breast Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Jian-Hua Shi
- Department of Thyroid and Breast Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu, China.
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Cao R, Tang W, Chen S. Association between BTLA polymorphisms and susceptibility to esophageal squamous cell carcinoma in the Chinese population. J Clin Lab Anal 2020; 34:e23221. [PMID: 32060969 PMCID: PMC7307356 DOI: 10.1002/jcla.23221] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/09/2019] [Accepted: 12/29/2019] [Indexed: 12/13/2022] Open
Abstract
Background Growing evidence suggested that B‐ and T‐lymphocyte attenuator (BTLA) polymorphisms raised the susceptibility to a wide range of cancers. This study aimed to evaluate whether BTLA variants were related to the risk of esophageal squamous cell carcinoma (ESCC). Methods A total of 721 ESCC patients and 1208 matched non‐cancer controls were included in this research, and four tagging BTLA polymorphisms (rs2171513 G > A, rs3112270 A > G, rs1982809 G > A, and rs16859629 T > C) were selected and genotyped using SNPscan™ Assays. Results In the present study, no significant relationship between BTLA polymorphisms and ESCC was observed. However, stratified analyses suggested that the variant of BTLA rs3112270 A > G reduced the risk of ESCC in the male subgroup (AG vs AA: adjusted OR = 0.78, 95% CI = 0.61‐0.99, P = .042), BMI < 24 kg/m2 subgroup (AG vs AA: adjusted OR = 0.72, 95% CI = 0.55‐0.93, P = .012; AG/GG vs AA: adjusted OR = 0.77, 95% CI = 0.60‐0.98, P = .032), and ever drinking subgroup (AG vs AA: adjusted OR = 0.61, 95% CI = 0.38‐0.97, P = .037). But when stratified by BMI ≥ 24 kg/m2, the rs3112270 A > G polymorphism increased the susceptibility to ESCC (GG vs AA: adjusted OR = 1.91, 95% CI = 1.02‐3.59, P = .045). Besides, we demonstrated that BTLA rs2171513 G > A polymorphism was protective of ESCC in the ever drinking subgroup (GA/AA vs GG: adjusted OR = 0.62, 95% CI = 0.39‐0.97, P = .037). Conclusion Taken together, our initial investigation postulated that the rs3112270 A > G and rs2171513 G > A variants in the BTLA gene are candidates for the risk of ESCC, which might be helpful for the early diagnosis and treatment of ESCC.
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Affiliation(s)
- Rui Cao
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Weifeng Tang
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Shuchen Chen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
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