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Gu Y, Li T, Zhang M, Chen J, Shen F, Ding J, Zhou G, Hua K. The Display between HPV Infection and Host Immunity in Cervical Cancer. FRONT BIOSCI-LANDMRK 2024; 29:426. [PMID: 39735976 DOI: 10.31083/j.fbl2912426] [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: 06/17/2024] [Revised: 07/20/2024] [Accepted: 08/06/2024] [Indexed: 12/31/2024]
Abstract
Most cervical cancers are related to the persistent infections of high-risk Human Papillomavirus (HPV) infections. Increasing evidence has witnessed the immunosuppressive effectiveness of HPV in the oncogenesis steps and progression steps. Here we review the immune response in HPV-related cervical malignancies and discuss the crosstalk between HPVs and the host immune response. Furthermore, we describe the identification and development of current immunotherapies in cervical cancer. Above all, we hope to provide a novel insight of the display between HPV infections and the host immune system.
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Affiliation(s)
- Yuanyuan Gu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Tingting Li
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
| | - Menglei Zhang
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Junhao Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Fang Shen
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Jingxin Ding
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Guannan Zhou
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
| | - Keqin Hua
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
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Zhang J, Zhan J, Guan Z, Lin X, Li T, Li M, Zhang C, Zhong L. The prognostic value of Th17/Treg cell in cervical cancer: a systematic review and meta-analysis. Front Oncol 2024; 14:1442103. [PMID: 39324000 PMCID: PMC11422014 DOI: 10.3389/fonc.2024.1442103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 08/26/2024] [Indexed: 09/27/2024] Open
Abstract
Background The prognostic significance of Treg and Th17 cells, as well as their ratio (Th17/Treg), in cervical cancer remains a topic of debate. Our study aimed to clarify their association with patient survival and clinical outcomes in cervical cancer through a comprehensive meta-analysis. Materials and methods We conducted a comprehensive search in PubMed, Embase, and Web of Science to identify eligible studies. Studies related to cervical cancer and involving Treg cells or Th17 cells were included. For prognostic analysis, we collected Hazard Ratio values of patient survival. For studies focusing on clinical characteristics, we selected mean and standard deviation values for further analysis. This study was registered at PROSPERO (ID:CRD42024546507). Results Out of the 2949 records initially retrieved, we ultimately included 21 studies in our analysis. High levels of Treg cells were found to be correlated with shorter survival in patients with cervical cancer. Subgroup analysis revealed that the prognostic effect of Treg cells on cervical cancer was not influenced by their source or definition. However, analyses of different survival measures indicated that only Overall Survival showed a correlation with Treg cell levels. Additionally, Treg cells were associated with clinical staging. High-grade Th17 cells were associated with lymphatic metastases and advanced clinical stage. The Th17/Treg ratio was found to be elevated in both cervical intraepithelial neoplasia and cervical cancer patients compared to controls. Discussion Despite limitations such as heterogeneity among selected studies and inadequate subgroup analyses, our study contributes to a deeper understanding of the significance of Treg cells in the onset and progression of cervical cancer. It also provides valuable insights for future research in immunotherapy. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024546507.
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Affiliation(s)
- Jingwei Zhang
- Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Jijie Zhan
- Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Ziting Guan
- Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Xinmei Lin
- Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Tian Li
- Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Miao Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Department of Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Changlin Zhang
- Department of Gynecology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Li Zhong
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Department of Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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Yu R, Wang S, Han L. Relevance of harmful intratumoral microbiota in cancer progression and its clinical application. Biomed Pharmacother 2024; 178:117238. [PMID: 39106707 DOI: 10.1016/j.biopha.2024.117238] [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: 06/06/2024] [Revised: 07/22/2024] [Accepted: 07/30/2024] [Indexed: 08/09/2024] Open
Abstract
Microorganisms are closely related to human health, and changes in the microbiome can lead to the occurrence of diseases. With advances in sequencing technology and research, it has been discovered that intratumoral microbiota exists in various cancer tissues and differs in various cancers. Microorganism can colonize tumor tissues through intestine of damaged mucosal barrier, proximity to normal tissues and bloodstream circulation. Increasing evidence suggests that intratumoral microbiota promotes tumor progression by increasing genomic instability, affecting host immune systems, promoting tumor migration, and regulating tumor signaling pathways. This review article summarizes the latest progress in intratumoral microbiome research, including the development history of intratumoral microbiota, their composition and sources within tumors, their distribution in various cancer tissues, as well as their role in cancer development. Furthermore, the application of intratumoral microbiota in clinical settings is emphasized and we innovatively summarize the clinical trials involving microbial applications for cancer diagnosis and treatment across different countries.
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Affiliation(s)
- Runze Yu
- Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Sheng Wang
- School of Life Sciences, Tianjin University, Tianjin 300072, China.
| | - Lei Han
- Tianjin Neurological Institute, Key Laboratory of Post-Neuro injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Al Assaad M, Safa H, Mercinelli C, Spiess PE, Necchi A, Chahoud J. Immune-based Therapies for Penile Cancer. Urol Clin North Am 2024; 51:355-365. [PMID: 38925738 DOI: 10.1016/j.ucl.2024.03.014] [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] [Indexed: 06/28/2024]
Abstract
This article reviews penile squamous cell carcinoma (PSCC), a rare genitourinary cancer that has been increasing in prevalence. It discusses emerging therapies, focusing on immunotherapy, vaccine therapy, and cell-based treatments, especially in the context of human papillomavirus-related PSCC. Factors influencing these therapies are discussed. These include the immune microenvironment, programmed cell death ligand-1 expression, and tumor immune cell infiltration. This article also highlights immune checkpoint inhibitors and related clinical trials. This review supports the use of personalized medicine in treating PSCC. It stresses the need for collaborative studies and data sharing to create specific treatment plans and achieve better outcomes.
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Affiliation(s)
- Majd Al Assaad
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 413 East 69th Street, Belfer Research Building, New York, NY 10021, USA.
| | - Houssein Safa
- Department of Hematology/Oncology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Chiara Mercinelli
- Department of Medical Oncology, IRCCS San Raffaele Hospital; Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Via Olgettina 60, Milan 20132, Italy
| | - Philippe E Spiess
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive office 12538, Tampa, FL 33612, USA
| | - Andrea Necchi
- Department of Medical Oncology, IRCCS San Raffaele Hospital; Vita-Salute San Raffaele University, Via Olgettina 60, Milan 20132, Italy
| | - Jad Chahoud
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive office 12538, Tampa, FL 33612, USA.
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Liu W, Li Y, Wu P, Guo X, Xu Y, Jin L, Zhao D. The intratumoral microbiota: a new horizon in cancer immunology. Front Cell Infect Microbiol 2024; 14:1409464. [PMID: 39135638 PMCID: PMC11317474 DOI: 10.3389/fcimb.2024.1409464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/01/2024] [Indexed: 08/15/2024] Open
Abstract
Over the past decade, advancements in high-throughput sequencing technologies have led to a qualitative leap in our understanding of the role of the microbiota in human diseases, particularly in oncology. Despite the low biomass of the intratumoral microbiota, it remains a crucial component of the tumor immune microenvironment, displaying significant heterogeneity across different tumor tissues and individual patients. Although immunotherapy has emerged a major strategy for treating tumors, patient responses to these treatments vary widely. Increasing evidence suggests that interactions between the intratumoral microbiota and the immune system can modulate host tumor immune responses, thereby influencing the effectiveness of immunotherapy. Therefore, it is critical to gain a deep understanding of how the intratumoral microbiota shapes and regulates the tumor immune microenvironment. Here, we summarize the latest advancements on the role of the intratumoral microbiota in cancer immunity, exploring the potential mechanisms through which immune functions are influenced by intratumoral microbiota within and outside the gut barrier. We also discuss the impact of the intratumoral microbiota on the response to cancer immunotherapy and its clinical applications, highlighting future research directions and challenges in this field. We anticipate that the valuable insights into the interactions between cancer immunity and the intratumoral microbiota provided in this review will foster the development of microbiota-based tumor therapies.
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Affiliation(s)
- Wei Liu
- College of Laboratory Medicine, Jilin Medical University, Jilin, China
| | - Yuming Li
- College of Laboratory Medicine, Jilin Medical University, Jilin, China
| | - Ping Wu
- General Surgery Department of Liaoyuan Central Hospital, Jilin, China
| | - Xinyue Guo
- College of Laboratory Medicine, Jilin Medical University, Jilin, China
| | - Yifei Xu
- College of Laboratory Medicine, Jilin Medical University, Jilin, China
| | - Lianhai Jin
- Low Pressure and Low Oxygen Environment and Health Intervention Innovation Center, Jilin Medical University, Jilin, China
| | - Donghai Zhao
- College of Basic Medicine, Jilin Medical University, Jilin, China
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Cao Y, Xia H, Tan X, Shi C, Ma Y, Meng D, Zhou M, Lv Z, Wang S, Jin Y. Intratumoural microbiota: a new frontier in cancer development and therapy. Signal Transduct Target Ther 2024; 9:15. [PMID: 38195689 PMCID: PMC10776793 DOI: 10.1038/s41392-023-01693-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/20/2023] [Accepted: 10/24/2023] [Indexed: 01/11/2024] Open
Abstract
Human microorganisms, including bacteria, fungi, and viruses, play key roles in several physiological and pathological processes. Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms, which have been confirmed to be closely related to oncogenesis. The concept of intratumoural microbiota was subsequently proposed. Microbiota could colonise tumour tissues through mucosal destruction, adjacent tissue migration, and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment. Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations, affecting epigenetic modifications, promoting inflammation response, avoiding immune destruction, regulating metabolism, and activating invasion and metastasis. Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging, new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination. In addition, interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy, especially immunotherapy, although there are some inevitable challenges. Here, we aim to provide an extensive review of the concept, development history, potential sources, heterogeneity, and carcinogenic mechanisms of intratumoural microorganisms, explore the potential role of microorganisms in tumour prognosis, and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.
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Affiliation(s)
- Yaqi Cao
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Hui Xia
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Xueyun Tan
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Chunwei Shi
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Yanling Ma
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Daquan Meng
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Mengmeng Zhou
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Zhilei Lv
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Sufei Wang
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
| | - Yang Jin
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
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Trujillo-Cirilo L, Weiss-Steider B, Vargas-Angeles CA, Corona-Ortega MT, Rangel-Corona R. Immune microenvironment of cervical cancer and the role of IL-2 in tumor promotion. Cytokine 2023; 170:156334. [PMID: 37598478 DOI: 10.1016/j.cyto.2023.156334] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 07/06/2023] [Accepted: 08/11/2023] [Indexed: 08/22/2023]
Abstract
The tumor microenvironment (TME) is a heterogeneous mixture of resident and tumor cells that maintain close communication through their secretion products. The composition of the TME is dynamic and complex among the different types of cancer, where the immune cells play a relevant role in the elimination of tumor cells, however, under certain circumstances they contribute to tumor development. In cervical cancer (CC) the human papilloma virus (HPV) shapes the microenvironment in order to mediate persistent infections that favors transformation and tumor development. Interleukin-2 (IL-2) is an important TME cytokine that induces CD8+ effector T cells and NKs to eliminate tumor cells, however, IL-2 can also suppress the immune response through Treg cells. Recent studies have shown that CC cells express the IL-2 receptor (IL-2R), that are induced to proliferate at low concentrations of exogenous IL-2 through alterations in the JAK/STAT pathway. This review provides an overview of the main immune cells that make up the TME in CC, as well as the participation of IL-2 in the tumor promotion. Finally, it is proposed that the low density of IL-2 produced by immunocompetent cells is used by tumor cells through its IL-2R as a mechanism to proliferate simultaneously depleting this molecule in order to evade immune response.
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Affiliation(s)
- Leonardo Trujillo-Cirilo
- Laboratory of Cellular Oncology, Research Unit Cell Differentiation and Cancer, L-4 P.B. FES Zaragoza, National University of Mexico, Av., Guelatao No. 66 Col. Ejercito de Oriente, Iztapalapa, C.P. 09230 Mexico City, Mexico.
| | - Benny Weiss-Steider
- Laboratory of Cellular Oncology, Research Unit Cell Differentiation and Cancer, L-4 P.B. FES Zaragoza, National University of Mexico, Av., Guelatao No. 66 Col. Ejercito de Oriente, Iztapalapa, C.P. 09230 Mexico City, Mexico
| | - Carlos Adrian Vargas-Angeles
- Laboratory of Cellular Oncology, Research Unit Cell Differentiation and Cancer, L-4 P.B. FES Zaragoza, National University of Mexico, Av., Guelatao No. 66 Col. Ejercito de Oriente, Iztapalapa, C.P. 09230 Mexico City, Mexico
| | - Maria Teresa Corona-Ortega
- Laboratory of Cellular Oncology, Research Unit Cell Differentiation and Cancer, L-4 P.B. FES Zaragoza, National University of Mexico, Av., Guelatao No. 66 Col. Ejercito de Oriente, Iztapalapa, C.P. 09230 Mexico City, Mexico
| | - Rosalva Rangel-Corona
- Laboratory of Cellular Oncology, Research Unit Cell Differentiation and Cancer, L-4 P.B. FES Zaragoza, National University of Mexico, Av., Guelatao No. 66 Col. Ejercito de Oriente, Iztapalapa, C.P. 09230 Mexico City, Mexico
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Chetty-Sebastian D, Assounga AG. Regulatory T cell frequency in peripheral blood of women with advanced cervical Cancer including women living with HIV. BMC Cancer 2023; 23:830. [PMID: 37670247 PMCID: PMC10481519 DOI: 10.1186/s12885-023-11345-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/28/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND Persistent high-risk Human papillomavirus (HR-HPV) infections are the main cause of cervical cancer. Cumulative evidence implicates regulatory T cells (Tregs) as a critical factor in the failure to eliminate HPV-induced cancers leading to their persistence and progression to cancer. Also, the WHO recognised cervical cancer as 100% attributable to persistent HR-HPV infection. The province of KwaZulu-Natal (KZN) in South Africa has a high prevalence of cervical cancer and HIV infection. MATERIALS AND METHODS We evaluated Treg frequency in dual infection of HR HPV and HIV coinfection using phenotypic markers, CD4, CD25 and intracellular Foxp3, in the peripheral blood of 51 cervical cancer and 46 non-cervical cancer participants and evaluated the effect of HIV on regulatory T cell proportion. Peripheral blood mononuclear cells were surface stained with a cocktail fluorescent labelled CD4 and CD25 and subsequently with APC anti-human FoxP3 (eBioscience). Flow cytometry was performed with FACS analysis. Statistical analysis of results was done using Instat 3 program (GraphpadR). Tregs results were expressed as median ± interquartile range (IQR). Associations of cervical cancer with demographic, clinical and laboratory variables were evaluated by univariate and multivariate logistic regression analysis using SPSS version 27 (IBM). RESULTS Tregs frequency was significantly higher in individuals with cervical cancer (11.00 ± 19.79%) compared to controls (1.71 ± 8.91%) (p < 0.0001). HIV infection was associated with an increase in Tregs frequency. In controls a significant difference in Tregs frequency was noted between women living with HIV (6.00 ± 10.57%, n = 9) and those without HIV (1.30 ± 6.10%, n = 37), p = 0.0023. In multivariate logistic regression, Tregs frequency was significantly associated with cervical cancer after controlling for age, smoking, weight loss, presence of STI, HIV and HPV genotype. DISCUSSION/CONCLUSION Higher Tregs frequency was significantly associated with cervical cancer highlighting the immunosuppressive role of Tregs in cervical cancer. Treg frequency was more strongly associated with cervical cancer than HIV infection. We provide baseline data for monitoring Treg frequencies in response to new preventive and therapeutic strategies in the management of cervical cancer.
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Affiliation(s)
- Devamani Chetty-Sebastian
- Clinical Medicine laboratory, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4001 South Africa
| | - Alain G. Assounga
- Clinical Medicine laboratory, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4001 South Africa
- Dept of Nephrology, Div. of Internal Medicine, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4001 South Africa
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Liu L, Xie Y, Yang H, Lin A, Dong M, Wang H, Zhang C, Liu Z, Cheng Q, Zhang J, Yuan S, Luo P. HPVTIMER: A shiny web application for tumor immune estimation in human papillomavirus-associated cancers. IMETA 2023; 2:e130. [PMID: 38867938 PMCID: PMC10989930 DOI: 10.1002/imt2.130] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/14/2023] [Accepted: 06/19/2023] [Indexed: 06/14/2024]
Abstract
The tumor immune microenvironment (TIME) is closely associated with tumor formation, particularly linked to the human papillomavirus (HPV), and regulates tumor initiation, proliferation, infiltration, and metastasis. With the rise of immunotherapy, an increasing amount of sample data used for TIME exploration is available in databases. However, no currently available web tool enables a comprehensive exploration of the TIME of HPV-associated cancers by leveraging these data. We have developed a web tool called HPV-associated Tumor Immune MicroEnvironment ExploreR (HPVTIMER), which provides a comprehensive analysis platform that integrates over 10,000 genes and 2290 tumor samples from 65 transcriptome data sets across 8 cancer types sourced from the Gene Expression Omnibus (GEO) database. The tool features four built-in analysis modules, namely, the differential expression analysis module, correlation analysis module, immune infiltration analysis module, and pathway analysis module. These modules enable users to perform systematic and vertical analyses. We used several analytical modules in HPVTIMER to briefly explore the role of CDKN2A in head and neck squamous cell carcinomas. We expect that HPVTIMER will help users explore the immune microenvironment of HPV-associated cancers and uncover potential immune regulatory mechanisms and immunotherapeutic targets. HPVTIMER is available at http://www.hpvtimer.com/.
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Affiliation(s)
- Liying Liu
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
- The First Clinical Medical SchoolSouthern Medical UniversityGuangzhouGuangdongChina
| | - Yanan Xie
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
- The Second Clinical Medicine SchoolSouthern Medical UniversityGuangzhouGuangdongChina
| | - Hong Yang
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Anqi Lin
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Minjun Dong
- Department of Surgical OncologySir Run Run Shaw Hospital Affiliated to Zhejiang University, School of MedicineHang ZhouChina
| | - Haitao Wang
- Thoracic Surgery BranchCenter for Cancer Research, National Institutes of HealthBethesdaMarylandUSA
| | - Cangang Zhang
- Department of Pathogenic Microbiology and ImmunologyXi'an Jiaotong UniversityXi'anShaanxiChina
| | - Zaoqu Liu
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Quan Cheng
- Department of NeurosurgeryXiangya Hospital, Central South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityHunanChina
| | - Jian Zhang
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
| | - Shuofeng Yuan
- Department of Infectious Disease and MicrobiologyThe University of Hong Kong‐Shenzhen HospitalShenzhenChina
- State Key Laboratory of Emerging Infectious Diseases, Department of MicrobiologySchool of Clinical Medicine, Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong KongHong KongChina
| | - Peng Luo
- Department of OncologyZhujiang Hospital, Southern Medical UniversityGuangzhouGuangdongChina
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Glover A, Zhang Z, Shannon-Lowe C. Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis. Front Immunol 2023; 14:1161848. [PMID: 37033972 PMCID: PMC10076641 DOI: 10.3389/fimmu.2023.1161848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/10/2023] [Indexed: 04/11/2023] Open
Abstract
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid cells derived from monocyte and granulocyte precursors. They are pathologically expanded in conditions of ongoing inflammation where they function to suppress both innate and adaptive immunity. They are subdivided into three distinct subsets: monocytic (M-) MDSC, polymorphonuclear (or neutrophilic) (PMN-) MDSC and early-stage (e-) MDSC that may exhibit differential function in different pathological scenarios. However, in cancer they are associated with inhibition of the anti-tumour immune response and are universally associated with a poor prognosis. Seven human viruses classified as Group I carcinogenic agents are jointly responsible for nearly one fifth of all human cancers. These viruses represent a large diversity of species, including DNA, RNA and retroviridae. They include the human gammaherpesviruses (Epstein Barr virus (EBV) and Kaposi's Sarcoma-Associated Herpesvirus (KSHV), members of the high-risk human papillomaviruses (HPVs), hepatitis B and C (HBV, HCV), Human T cell leukaemia virus (HTLV-1) and Merkel cell polyomavirus (MCPyV). Each of these viruses encode an array of different oncogenes that perturb numerous cellular pathways that ultimately, over time, lead to cancer. A prerequisite for oncogenesis is therefore establishment of chronic infection whereby the virus persists in the host cells without being eradicated by the antiviral immune response. Although some of the viruses can directly modulate the immune response to enable persistence, a growing body of evidence suggests the immune microenvironment is modulated by expansions of MDSCs, driven by viral persistence and oncogenesis. It is likely these MDSCs play a role in loss of immune recognition and function and it is therefore essential to understand their phenotype and function, particularly given the increasing importance of immunotherapy in the modern arsenal of anti-cancer therapies. This review will discuss the role of MDSCs in viral oncogenesis. In particular we will focus upon the mechanisms thought to drive the MDSC expansions, the subsets expanded and their impact upon the immune microenvironment. Importantly we will explore how MDSCs may modulate current immunotherapies and their impact upon the success of future immune-based therapies.
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11
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Guo Q, Chen W, Sun J, Zhao C, Bai X, Zhang Y, Liu K, Zhang L, Shao S. Nocardia rubra cell-wall skeleton activates an immune response in cervical tissue via stimulating FPR3 to enhance dendritic cell-mediated Th1 differentiation. Front Immunol 2023; 14:1117545. [PMID: 36936958 PMCID: PMC10018199 DOI: 10.3389/fimmu.2023.1117545] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
Nocardia rubra cell wall skeleton (Nr-CWS) has proven to be a successful medicine for therapy of cervical human papillomavirus infection. The mechanism of action of Nr-CWS is unclear but may involve a stimulatory effect on the host immune system. We previously found that CD4+ T cells were increased in cervical tissue after Nr-CWS treatment. Microarray data from these cervical tissues revealed the significant upregulation of formylated peptide receptor 3 (FPR3). This study aimed to explore the role of Nr-CWS in immunomodulatory based on these findings. Examination of CD4+ T cell subsets in cervical tissue from patients who received Nr-CWS revealed substantial increases in Th1 cytokines and transcription factors. The regulatory effects of Nr-CWS on the function and phenotype of dendritic cells (DCs) were assessed in comparison with the traditional DC maturation inducer lipopolysaccharide (LPS). Similar to LPS, Nr-CWS potently induced DC maturation and interleukin-12 (IL-12) secretion. Differentiation of T cells induced by Nr-CWS stimulated DCs was assessed using the mixed lymphocyte reaction assay. Significant differentiation towards Th1 was evident. Finally, FPR3 expression in DCs in response to Nr-CWS and LPS was measured. Nr-CWS potently upregulated FPR3 expression, while the LPS did not. Silencing FPR3 in DCs reduced Nr-CWS-induced IL-12 production and Th1 cell polarization in co-cultured T cells. The collective findings indicate that Nr-CWS may target FPR3 on the surface of DC cells and activate a Th1-type immune response. The findings clarify the basis of the antiviral immune effects of Nr-CWS on human papillomavirus.
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Affiliation(s)
- Qianyu Guo
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
| | - Wei Chen
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
| | - Junyi Sun
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
| | - Chunfang Zhao
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
| | - Xue Bai
- Department of Gynecology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanan Zhang
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
| | - Ke Liu
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
| | - Lei Zhang
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
- *Correspondence: Lei Zhang, ; Suxia Shao,
| | - Suxia Shao
- Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China
- *Correspondence: Lei Zhang, ; Suxia Shao,
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12
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Enhancing the Effect of Nucleic Acid Vaccines in the Treatment of HPV-Related Cancers: An Overview of Delivery Systems. Pathogens 2022; 11:pathogens11121444. [PMID: 36558778 PMCID: PMC9781236 DOI: 10.3390/pathogens11121444] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/05/2022] Open
Abstract
Prophylactic vaccines against human papillomavirus (HPV) have proven efficacy in those who have not been infected by the virus. However, they do not benefit patients with established tumors. Therefore, the development of therapeutic options for HPV-related malignancies is critical. Third-generation vaccines based on nucleic acids are fast and simple approaches to eliciting adaptive immune responses. However, techniques to boost immunogenicity, reduce degradation, and facilitate their capture by immune cells are frequently required. One option to overcome this constraint is to employ delivery systems that allow selective antigen absorption and help modulate the immune response. This review aimed to discuss the influence of these different systems on the response generated by nucleic acid vaccines. The results indicate that delivery systems based on lipids, polymers, and microorganisms such as yeasts can be used to ensure the stability and transport of nucleic acid vaccines to their respective protein synthesis compartments. Thus, in view of the limitations of nucleic acid-based vaccines, it is important to consider the type of delivery system to be used-due to its impact on the immune response and desired final effect.
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13
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Muntinga CLP, de Vos van Steenwijk PJ, Bekkers RLM, van Esch EMG. Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy. J Clin Med 2022; 11:jcm11051432. [PMID: 35268523 PMCID: PMC8910829 DOI: 10.3390/jcm11051432] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/10/2022] Open
Abstract
Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in the pathogenesis, spontaneous regression, and progression of cervical dysplasia; however, the underlying mechanisms are unknown. The aim of this review is to outline the changes in the immune microenvironment in spontaneous regression, persistence, and responses to (immuno)therapy. In lesion persistence and progression, the immune microenvironment of cHSIL is characterized by a lack of intraepithelial CD3+, CD4+, and CD8+ T cell infiltrates and Langerhans cells compared to the normal epithelium and by an increased number of CD25+FoxP3+ regulatory T cells (Tregs) and CD163+ M2 macrophages. Spontaneous regression is characterized by low numbers of Tregs, more intraepithelial CD8+ T cells, and a high CD4+/CD25+ T cell ratio. A ‘hot’ immune microenvironment appears to be essential for spontaneous regression of cHSIL. Moreover, immunotherapy, such as imiquimod and therapeutic HPV vaccination, may enhance a preexisting pro-inflammatory immune environment contributing to lesion regression. The preexisting immune composition may reflect the potential for lesion regression, leading to a possible immune biomarker for immunotherapy in cHSILs.
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Affiliation(s)
- Caroline L. P. Muntinga
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
| | - Peggy J. de Vos van Steenwijk
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
- Department of Gynecology and Obstetrics, Maastricht Universitair Medisch Centrum, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Ruud L. M. Bekkers
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- GROW—School for Oncology and Reproduction, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands;
| | - Edith M. G. van Esch
- Department of Gynecology and Obstetrics, Catharina Ziekenhuis Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands; (C.L.P.M.); (R.L.M.B.)
- Correspondence: ; Tel.: +31-402-399-111
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14
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Role of FoxP3-positive regulatory T-cells in regressive and progressive cervical dysplasia. J Cancer Res Clin Oncol 2021; 148:377-386. [PMID: 34739585 DOI: 10.1007/s00432-021-03838-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 09/14/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE Forkhead Box Protein 3 (FoxP3) is known as a key mediator in the immunosuppressive function of regulatory T-cells (Tregs). The aim of our study was to investigate whether FoxP3-positive Tregs have the potential to act as an independent predictor in progression as well as in regression of cervical intraepithelial neoplasia, especially in patients with intermediate cervical intraepithelial neoplasia (CIN II). METHODS Nuclear FoxP3 expression was immunohistochemically analysed in 169 patient samples (CIN I, CIN II with regressive course, CIN II with progressive course, CIN III). The median numbers were calculated for each slide and correlated with the histological CIN grade. Statistical analysis was performed by SPSS 26 (Mann-Whitney U test, Spearman's rank correlation). RESULTS An increased FoxP3 expression in CIN II with progression could be detected in comparison to CIN II with regression (p = 0.003). Total FoxP3 expression (epithelium and dysplasia-connected stroma) was higher in more advanced CIN grades (p < 0.001 for CIN I vs. CIN II; p = 0.227 for CIN II vs. CIN III). A positive correlation could be detected between FoxP3-positive cells in epithelium and total FoxP3 expression (Spearman's Rho: 0,565; p < 0.01). CONCLUSION Expression of FoxP3 could be a helpful predictive factor to assess the risks of CIN II progression. As a prognosticator for regression and progression in cervical intraepithelial lesions it might thereby help in the decision process regarding surgical treatment vs. watchful waiting strategy to prevent conisation-associated risks for patients in child-bearing age. In addition, the findings support the potential of Tregs as a target for immune therapy in cervical cancer patients.
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15
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Xu F, Zhang F, Wang Q, Xu Y, Xu S, Zhang C, Wang L. The augment of regulatory T cells undermines the efficacy of anti-PD-L1 treatment in cervical cancer. BMC Immunol 2021; 22:60. [PMID: 34479503 PMCID: PMC8414724 DOI: 10.1186/s12865-021-00451-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 08/28/2021] [Indexed: 01/08/2023] Open
Abstract
Background Immune checkpoint inhibitors have aroused great expectation of tumor eradication. However, the effect of anti-PD-L1 treatment for cervical cancer is unsatisfactory and the underlying antagonist to anti-PD-L1 efficacy is remained to be studied. Here, we investigated the anti-tumor effect of anti-PD-L1 treatment in cervical tumor model and identified the antagonist to the therapeutic efficacy of anti-PD-L1 treatment. Results We found that PD-L1 exhibited a moderate expression in both cervical tumor cell lines and clinical samples compared to other tumor types and the para-tumor tissue respectively. Interestingly, our results showed that the anti-PD-L1 treated mice were dichotomously divided into responsive and unresponsive group after five cycles of anti-PD-L1 treatment although all the mice had the same genome background. In addition, the unresponsive tumors showed less tumor necrosis area and higher immunosuppression activity induced by regulatory T cells (Tregs) population than the responsive ones. Furthermore, we found that anti-PD-L1 treatment autonomously upregulated Tregs proliferation and frequency in multiple immune organs, and, most importantly, Tregs depletion significantly depressed the tumor growth rate and tumor weight compared with either anti-PD-L1 or anti-CD25 treatment alone. Finally, we observed that the upregulating effector CD8+ T cell is associated with the better therapeutic effect of anti-PD-L1 therapy post Tregs depletion. Conclusions Anti-PD-L1 treatment upregulates Tregs frequency and proliferation in tumor model, and the depletion of Tregs may be a useful adjuvant strategy for anti-PD-L1 therapy of cervical cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12865-021-00451-7.
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Affiliation(s)
- Fengying Xu
- Department of Gynaecology and Obstetrics, Jinshan District Tinglin Hospital, Shanghai, 201505, China
| | - Fengying Zhang
- Department of Gynaecology and Obstetrics, Jinshan District Tinglin Hospital, Shanghai, 201505, China
| | - Qian Wang
- Department of Pathology, Jinshan District Tinglin Hospital, Shanghai, 201505, China
| | - Ying Xu
- Department of Gynaecology and Obstetrics, Jinshan District Tinglin Hospital, Shanghai, 201505, China
| | - Shuifang Xu
- Department of Gynaecology and Obstetrics, Jinshan District Tinglin Hospital, Shanghai, 201505, China
| | - Caihong Zhang
- Department of Gynaecology and Obstetrics, Jinshan District Tinglin Hospital, Shanghai, 201505, China
| | - Lihua Wang
- Department of Gynecologic Oncology, International Peace Maternity & Child Health Hospital, Shanghai JiaoTong University School of Medicine, 910 Hengshan Road, Xuhui District, Shanghai, 200030, China.
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16
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Shamseddine AA, Burman B, Lee NY, Zamarin D, Riaz N. Tumor Immunity and Immunotherapy for HPV-Related Cancers. Cancer Discov 2021; 11:1896-1912. [PMID: 33990345 PMCID: PMC8338882 DOI: 10.1158/2159-8290.cd-20-1760] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/27/2021] [Accepted: 03/16/2021] [Indexed: 12/17/2022]
Abstract
Human papillomavirus (HPV) infection drives tumorigenesis in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Genetic and epidemiologic evidence has highlighted the role of immunosuppression in the oncogenesis of HPV-related malignancies. Here we review how HPV modulates the immune microenvironment and subsequent therapeutic implications. We describe the landscape of immunotherapies for these cancers with a focus on findings from early-phase studies exploring antigen-specific treatments, and discuss future directions. Although responses across these studies have been modest to date, a deeper understanding of HPV-related tumor biology and immunology may prove instrumental for the development of more efficacious immunotherapeutic approaches. SIGNIFICANCE: HPV modulates the microenvironment to create a protumorigenic state of immune suppression and evasion. Our understanding of these mechanisms has led to the development of immunomodulatory treatments that have shown early clinical promise in patients with HPV-related malignancies. This review summarizes our current understanding of the interactions of HPV and its microenvironment and provides insight into the progress and challenges of developing immunotherapies for HPV-related malignancies.
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Affiliation(s)
- Achraf A Shamseddine
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Bharat Burman
- Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy Y Lee
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dmitriy Zamarin
- Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Nadeem Riaz
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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17
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R S J. The Immune Microenvironment in Human Papilloma Virus-Induced Cervical Lesions-Evidence for Estrogen as an Immunomodulator. Front Cell Infect Microbiol 2021; 11:649815. [PMID: 33996630 PMCID: PMC8120286 DOI: 10.3389/fcimb.2021.649815] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/29/2021] [Indexed: 12/24/2022] Open
Abstract
Globally, human papilloma virus (HPV) infection is a common sexually transmitted disease. However, most of the HPV infections eventually resolve aided by the body’s efficient cell-mediated immune responses. In the vast majority of the small group of patients who develop overt disease too, it is the immune response that culminates in regression of lesions. It is therefore a rarity that persistent infection by high-risk genotypes of HPV compounded by other risk factors progresses through precancer (various grades of cervical intraepithelial neoplasia—CIN) to cervical cancer (CxCa). Hence, although CxCa is a rare culmination of HPV infection, the latter is nevertheless causally linked to >90% of cancer. The three ‘Es’ of cancer immunoediting viz. elimination, equilibrium, and escape come into vogue during the gradual evolution of CIN 1 to CxCa. Both cell-intrinsic and extrinsic mechanisms operate to eliminate virally infected cells: cell-extrinsic players are anti-tumor/antiviral effectors like Th1 subset of CD4+ T cells, CD8+ cytotoxic T cells, Natural Killer cells, etc. and pro-tumorigenic/immunosuppressive cells like regulatory T cells (Tregs), Myeloid-Derived Suppressor Cells (MDSCs), type 2 macrophages, etc. And accordingly, when immunosuppressive cells overpower the effectors e.g., in high-grade lesions like CIN 2 or 3, the scale is tilted towards immune escape and the disease progresses to cancer. Estradiol has long been considered as a co-factor in cervical carcinogenesis. In addition to the gonads, the Peyer’s patches in the gut synthesize estradiol. Over and above local production of the hormone in the tissues, estradiol metabolism by the gut microbiome: estrobolome versus tryptophan non-metabolizing microbiome, regulates free estradiol levels in the intestine and extraintestinal mucosal sites. Elevated tissue levels of the hormone serve more than one purpose: besides a direct growth-promoting action on cervical epithelial cells, estradiol acting genomically via Estrogen Receptor-α also boosts the function of the stromal and infiltrating immunosuppressive cells viz. Tregs, MDSCs, and carcinoma-associated fibroblasts. Hence as a corollary, therapeutic repurposing of Selective Estrogen Receptor Disruptors or aromatase inhibitors could be useful for modulating immune function in cervical precancer/cancer. The immunomodulatory role of estradiol in HPV-mediated cervical lesions is reviewed.
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Affiliation(s)
- Jayshree R S
- Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India
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18
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Litwin TR, Irvin SR, Chornock RL, Sahasrabuddhe VV, Stanley M, Wentzensen N. Infiltrating T-cell markers in cervical carcinogenesis: a systematic review and meta-analysis. Br J Cancer 2021; 124:831-841. [PMID: 33257839 PMCID: PMC7884592 DOI: 10.1038/s41416-020-01184-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 10/22/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The host adaptive immune response helps determine which cervical HPV infections persist and progress to precancer and cancer, and systematic characterisation of T-cell infiltration would help inform key steps in cervical carcinogenesis. METHODS A systematic review and meta-analysis were conducted of infiltrating T-cells in normal cervix, low-grade lesions, high-grade lesions, and invasive cancers including epithelial, stromal, and total tissue and the following markers: CD3, CD4, CD8, FoxP3, CD25, and the CD4:CD8 ratio. An additional qualitative review summarised longitudinal data on associations between infiltrating T-cells and cervical disease persistence, regression, progression, or prognosis. RESULTS There were fewer CD3+, CD4+, and CD8+ cells in cervical lesions and more cells in cancers compared to normal epithelium. FoxP3 and CD25+ regulatory T-cell infiltration is high in persistent and precancerous lesions, and longitudinal data show improved outcomes with lower regulatory T-cell levels. CONCLUSIONS Successful immune evasion may reduce T-cell infiltration in HPV infected and precancerous epithelium, while invasive cancers are highly immunogenic, and regulatory T-cell infiltration increases with cervical disease progression. Understanding these factors may have prognostic value and could aid in novel treatment development and clinical guidelines, but published data are highly heterogeneous and leave important gaps to be filled by future studies.
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Affiliation(s)
- Tamara R Litwin
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
| | - Sarah R Irvin
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Rebecca L Chornock
- Department of Obstetrics and Gynecology, MedStar Washington Hospital Center, Washington, DC, USA
| | - Vikrant V Sahasrabuddhe
- Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA
| | | | - Nicolas Wentzensen
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
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19
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Britto AMA, Goes LR, Sivro A, Policarpo C, Meirelles ÂR, Furtado Y, Almeida G, Arthos J, Cicala C, Soares MA, Machado ES, Giannini ALM. HPV Induces Changes in Innate Immune and Adhesion Molecule Markers in Cervical Mucosa With Potential Impact on HIV Infection. Front Immunol 2020; 11:2078. [PMID: 33013878 PMCID: PMC7494736 DOI: 10.3389/fimmu.2020.02078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 07/30/2020] [Indexed: 12/03/2022] Open
Abstract
While most HPV infections are asymptomatic and clear spontaneously, persistent infection with high-risk HPVs is associated with cervical cancer and with increased risk of HIV acquisition. Although several hypotheses have been proposed to explain this phenomenon, none has been confirmed. Our aim was to investigate the expression of host factors involved in the susceptibility to HIV infection among HPV-infected women. Cervical samples were collected to characterize the expression levels of HIV susceptibility markers in the mucosa of HPV-infected compared with HPV-uninfected women. No differences in the frequency of CCR5+, integrin α4β7+, activated and memory CD4+ T-cell were detected between the groups. We additionally evaluated the expression levels of genes involved in innate immune responses and in cell adhesion. HPV infected patients expressed higher levels of TLR9 and lower levels of pattern recognition receptors that recognize RNA (TLR3, TLR7, and MDA5/IFIH1). We also detected an impaired IFN pathway, with an increased Type I IFN and a decreased IFNα2 receptor expression. HPV+ samples displayed reduced expression of genes for adherens and tight junctions. Taken together, these results suggest that although HPV infection does not result in the recruitment/activation of susceptible CD4+ T-cell in the female genital tract, it leads to changes in the innate antiviral immune responses and in cell adhesion that are likely to favor HIV infection.
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Affiliation(s)
- Alan Messala A Britto
- Programa de Oncovirologia, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.,Laboratório de Genômica Funcional e Transdução de Sinal, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Livia R Goes
- Programa de Oncovirologia, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.,Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Aida Sivro
- Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.,Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.,Department of Medical Microbiology, University of KwaZulu-Natal, Durban, South Africa
| | - Cintia Policarpo
- Laboratório de Genômica Funcional e Transdução de Sinal, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ângela R Meirelles
- Instituto de Ginecologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Yara Furtado
- Instituto de Ginecologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gutemberg Almeida
- Instituto de Ginecologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - James Arthos
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Claudia Cicala
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Marcelo A Soares
- Programa de Oncovirologia, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil
| | - Elizabeth S Machado
- Laboratório de Genômica Funcional e Transdução de Sinal, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Lúcia M Giannini
- Laboratório de Genômica Funcional e Transdução de Sinal, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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20
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Lin W, Zhang HL, Niu ZY, Wang Z, Kong Y, Yang XS, Yuan F. The disease stage-associated imbalance of Th1/Th2 and Th17/Treg in uterine cervical cancer patients and their recovery with the reduction of tumor burden. BMC WOMENS HEALTH 2020; 20:126. [PMID: 32552719 PMCID: PMC7301485 DOI: 10.1186/s12905-020-00972-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 05/10/2020] [Indexed: 01/21/2023]
Abstract
Background Nearly all uterine cervical cancer (UCC) cases result from human papillomavirus (HPV) infection. After high-risk HPV infection, most HPV infections are naturally cleared by humoral and cell-mediated immune responses. Thus, cervical lesions of only few patients progress into cervical cancer via cervical intraepithelial neoplasia (CIN) and lead to persistent oncogenic HPV infection. This suggests that immunoregulation plays an instrumental role in the carcinogenesis. However, there was a few studies on the relation between the immunologic dissonance and clinical characteristics of UCC patients. Method We examined the related immune cells (Th1, Th2, Th17, and Treg cells) by flow cytometric analysis and analyzed their relations with UCC stages, tumor size, differentiation, histology type, lymph node metastases, and vasoinvasion. Next, we quantified the Th1, Th2, Th17, and Treg cells before and after the operation both in UCC and CIN patients. Results When compared with stage I patients, decreased levels of circulating Th1 cells and elevated levels of Th2, Th17, and Treg cells were detected in stage II patients. In addition, the imbalance of Th1/Th2 and Th17/Treg cells was related to the tumor size, lymph node metastases, and vasoinvasion. We found that immunological cell levels normalized after the operations. In general, immunological cell levels in CIN patients normalized sooner than in UCC patients. Conclusions Our findings suggested that peripheral immunological cell levels reflect the patient’s condition.
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Affiliation(s)
- Wei Lin
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Hua-Ling Zhang
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Zhao-Yuan Niu
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Zhen Wang
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Yan Kong
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xing-Sheng Yang
- Department of Obstetrics and Gynecology, Qi Lu Hospital of Shandong University, Jinan, People's Republic of China.
| | - Fang Yuan
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China.
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21
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Yang H, Ye S, Goswami S, Li T, Wu J, Cao C, Ma J, Lu B, Pei X, Chen Y, Yu J, Xu H, Qiu L, Afridi S, Xiang L, Zhang X. Highly immunosuppressive HLADR hi regulatory T cells are associated with unfavorable outcomes in cervical squamous cell carcinoma. Int J Cancer 2019; 146:1993-2006. [PMID: 31709528 DOI: 10.1002/ijc.32782] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 10/16/2019] [Accepted: 10/28/2019] [Indexed: 12/21/2022]
Abstract
Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADRhi Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADRhi Tregs express high levels of a panel of inhibition and activation markers and the TCR-responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADRhi Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADRhi Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor-infiltrating HLADRhi Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context-based quantification revealed that a high frequency of stromal HLADRhi Tregs in patients is significantly associated with worse progression-free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADRhi Tregs in CSCC patients. An increased HLADRhi Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno-oncology studies.
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Affiliation(s)
- Huijuan Yang
- Department of Gynecological Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuang Ye
- Department of Gynecological Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shyamal Goswami
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Teng Li
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Jingwen Wu
- Department of Gynecological Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chunmei Cao
- Cancer Institute, Fudan University, Shanghai Cancer Center, Shanghai, China
| | - Jiaqiang Ma
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Bin Lu
- Rudong People's Hospital, Jiangsu, China
| | - Xuan Pei
- Department of Gynecological Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanan Chen
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Jing Yu
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Huihui Xu
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Liwei Qiu
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Saifullah Afridi
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.,Department of Biological Sciences (DBS), National University of Medical Sciences (NUMS), Secretariat c/o Military Hospital, Adjacent to Armed Force Institute of Cardiology, Rawalpindi, Pakistan
| | - Libing Xiang
- Department of Gynecological Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoming Zhang
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
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22
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Bashaw AA, Teoh SM, Tuong ZK, Leggatt GR, Frazer IH, Chandra J. HPV16 E7-Driven Epithelial Hyperplasia Promotes Impaired Antigen Presentation and Regulatory T-Cell Development. J Invest Dermatol 2019; 139:2467-2476.e3. [PMID: 31207230 DOI: 10.1016/j.jid.2019.03.1162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/15/2019] [Accepted: 03/31/2019] [Indexed: 01/21/2023]
Abstract
Human papillomaviruses infect keratinocytes and can lead to hyperproliferative dysplasia and malignant transformation if not cleared by the immune system. Human papillomavirus has evolved an array of mechanisms to evade and manipulate the immune system to improve replication efficiency and promote persistent infection. We here demonstrate that hyperproliferative skin expressing the high-risk human papillomavirus 16 E7 oncogene as a transgene drives immunomodulation of dendritic cells (DCs), resulting in reduced capacity to take up antigen and prime effector CD4+ T cell responses. The phenotype of DCs in the E7-expressing hyperproliferative skin was not reversible by activation through intradermal immunization. Naïve CD4+ T cells primed by E7-driven hyperproliferative skin acquired FoxP3 expression and an anergic phenotype. DC and T help modulation was dependent on E7-retinoblastoma protein interaction-driven epithelial hyperproliferation, rather than on expression of E7. Inhibition of binding of E7 to retinoblastoma protein, and of consequent epithelial hyperplasia, was associated with normal skin DC phenotype, and T helper type 1 effector responses to immunization were restored. We conclude that human papillomavirus-induced epithelial hyperplasia modulates epithelial DCs and inhibits T helper type 1 immunity while polarizing T-cell differentiation to a regulatory or anergic phenotype.
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Affiliation(s)
- Abate Assefa Bashaw
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Siok M Teoh
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Zewen K Tuong
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Graham R Leggatt
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Ian H Frazer
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia.
| | - Janin Chandra
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
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23
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Ao C, Zeng K. The role of regulatory T cells in pathogenesis and therapy of human papillomavirus-related diseases, especially in cancer. INFECTION GENETICS AND EVOLUTION 2018; 65:406-413. [PMID: 30172014 DOI: 10.1016/j.meegid.2018.08.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/13/2018] [Accepted: 08/15/2018] [Indexed: 12/19/2022]
Abstract
Human papillomavirus (HPV) is the most common sexually transmitted agent in the world. It can cause condyloma acuminatum, anogenital malignancies, and head and neck cancers. The host immune responses to HPV involve multiple cell types that have regulatory functions, and HPV-mediated changes to regulatory T cells (Tregs) in both the local lesion tissues and the circulatory system of patients have received considerable attention. The role of Tregs in HPV infections ranges from suppression of effector T cell (Teff) responses to protection of tissues from immune-mediated injury in different anatomic subsites. In this review, we explore the influence of Tregs in the immunopathology of HPV-related diseases and therapies targeting Tregs as novel approaches against HPV.
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Affiliation(s)
- Chunping Ao
- Department of Dermatology and Venereology, Nanfang hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kang Zeng
- Department of Dermatology and Venereology, Nanfang hospital, Southern Medical University, Guangzhou, 510515, China.
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24
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Ottenhof SR, Djajadiningrat RS, Thygesen HH, Jakobs PJ, Jóźwiak K, Heeren AM, de Jong J, Sanders J, Horenblas S, Jordanova ES. The Prognostic Value of Immune Factors in the Tumor Microenvironment of Penile Squamous Cell Carcinoma. Front Immunol 2018; 9:1253. [PMID: 29942303 PMCID: PMC6004546 DOI: 10.3389/fimmu.2018.01253] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 05/18/2018] [Indexed: 12/26/2022] Open
Abstract
The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 2.8, p = 0.03]. The only immune factor with different expression in HPV+ and HPV- tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). In the HPV- cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.
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Affiliation(s)
| | - Rosa Sanne Djajadiningrat
- Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Department of Urology, HagaZiekenhuis, Hague, Netherlands
| | - Helene Hoegsbro Thygesen
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, Netherlands
- Statistics, Department of Conservation, Hamilton, New Zealand
| | | | - Katarzyna Jóźwiak
- Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Anne Marijne Heeren
- Center for Gynecologic Oncology Amsterdam (CGOA), VU University Medical Center, Amsterdam, Netherlands
| | - Jeroen de Jong
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Joyce Sanders
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Simon Horenblas
- Department of Urology, Netherlands Cancer Institute, Amsterdam, Netherlands
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25
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Tuong ZK, Noske K, Kuo P, Bashaw AA, Teoh SM, Frazer IH. Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions. PAPILLOMAVIRUS RESEARCH (AMSTERDAM, NETHERLANDS) 2018; 5:6-20. [PMID: 29807614 PMCID: PMC5886957 DOI: 10.1016/j.pvr.2017.10.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/14/2017] [Accepted: 10/16/2017] [Indexed: 01/26/2023]
Abstract
Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines.
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Affiliation(s)
- Z K Tuong
- The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - K Noske
- The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - P Kuo
- The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - A A Bashaw
- The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - S M Teoh
- The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia
| | - I H Frazer
- The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
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26
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Woodham AW, Yan L, Skeate JG, van der Veen D, Brand HH, Wong MK, Da Silva DM, Kast WM. T cell ignorance is bliss: T cells are not tolerized by Langerhans cells presenting human papillomavirus antigens in the absence of costimulation. PAPILLOMAVIRUS RESEARCH 2018; 2:21-30. [PMID: 27182559 PMCID: PMC4862606 DOI: 10.1016/j.pvr.2016.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs. Here we demonstrate that Tregs were not induced by LCs presenting only signal 1, and through a series of in vitro immunizations show that CD8+ T cells receiving signal 1+2 from LCs weeks after consistently receiving signal 1 are capable of robust effector functions. Importantly, this indicates that T cells are not tolerized but instead remain ignorant to HPV, and are activated given the proper signals.
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Affiliation(s)
- Andrew W Woodham
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America
| | - Lisa Yan
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America
| | - Joseph G Skeate
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America
| | | | - Heike H Brand
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Michael K Wong
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Diane M Da Silva
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, California, United States of America
| | - W Martin Kast
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, California, United States of America
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27
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28
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Kuo P, Tuong ZK, Teoh SM, Frazer IH, Mattarollo SR, Leggatt GR. HPV16E7-Induced Hyperplasia Promotes CXCL9/10 Expression and Induces CXCR3 + T-Cell Migration to Skin. J Invest Dermatol 2017; 138:1348-1359. [PMID: 29277541 DOI: 10.1016/j.jid.2017.12.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/28/2017] [Accepted: 12/12/2017] [Indexed: 11/25/2022]
Abstract
Chemokines regulate tissue immunity by recruiting specific subsets of immune cells. Mice expressing the E7 protein of human papilloma virus 16 as a transgene from a keratin 14 promoter (K14.E7) show increased epidermal and dermal lymphocytic infiltrates, epidermal hyperplasia, and suppressed local immunity. Here, we show that CXCL9 and CXCL10 are overexpressed in non-hematopoietic cells in skin of K14.E7 mice when compared with non-transgenic animals, and recruit CXCR3+ lymphocytes to the hyperplastic skin. Overexpression of CXCL9 and CXCL10 is not observed in E7 transgenic mice with mutated Rb gene whose protein product cannot interact with E7 (K14.E7xRbΔL/ΔL) and in consequence lack hyperplastic epithelium. CXCR3+ T cells are preferentially recruited by CXCL9 and CXCL10 in supernatants of K14.E7 but not K14.E7xRbΔL/ΔL skin cultures in vitro. CXCR3 signalling promotes infiltration of a subset of effector T lymphocytes that enables donor lymphocyte deficient, E7-expressing skin graft rejection. Taken together, this suggests that recruitment of CXCR3+ T cells can be an important factor in the rejection of precancerous skin epithelium providing they can overcome local immunosuppressive mechanisms driven by skin-resident lymphocytes.
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Affiliation(s)
- Paula Kuo
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Zewen K Tuong
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Siok Min Teoh
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Ian H Frazer
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia.
| | - Stephen R Mattarollo
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Graham R Leggatt
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
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29
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Bordignon V, Di Domenico EG, Trento E, D'Agosto G, Cavallo I, Pontone M, Pimpinelli F, Mariani L, Ensoli F. How Human Papillomavirus Replication and Immune Evasion Strategies Take Advantage of the Host DNA Damage Repair Machinery. Viruses 2017; 9:v9120390. [PMID: 29257060 PMCID: PMC5744164 DOI: 10.3390/v9120390] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/14/2017] [Accepted: 12/16/2017] [Indexed: 12/11/2022] Open
Abstract
The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)-STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses.
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Affiliation(s)
- Valentina Bordignon
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Enea Gino Di Domenico
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Elisabetta Trento
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Giovanna D'Agosto
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Ilaria Cavallo
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Martina Pontone
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Fulvia Pimpinelli
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Luciano Mariani
- HPV Unit, Department of Gynaecologic Oncology, National Cancer Institute Regina Elena, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
| | - Fabrizio Ensoli
- Clinical Pathology and Microbiology Unit, San Gallicano Dermatology Institute, IRCCS, IFO, Via Elio Chianesi 53, 00144 Rome, Italy.
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30
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Adurthi S, Kumar MM, Vinodkumar HS, Mukherjee G, Krishnamurthy H, Acharya KK, Bafna UD, Uma DK, Abhishekh B, Krishna S, Parchure A, Alka M, Jayshree RS. Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer. Sci Rep 2017; 7:17289. [PMID: 29229929 PMCID: PMC5725534 DOI: 10.1038/s41598-017-17102-w] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 11/14/2017] [Indexed: 01/07/2023] Open
Abstract
Oestrogen controls Foxp3 expression in regulatory T cells (Treg cells) via a mechanism thought to involve oestrogen receptor alpha (ERα), but the molecular basis and functional impact of ERα signalling in Treg cells remain unclear. We report that ERα ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating Treg cells (CD4+CD25hiCD127low), whereas blocking ERα with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating Treg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ERα complexes to FOXP3 protein in CxCa-derived Treg cells. Chromatin immunoprecipitation analyses of male blood Treg cells revealed ERα occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2-mediated ERα signalling is critical for the sustenance of FOXP3 expression and Treg cell function in human CxCa via direct interaction of ERα with FOXP3 promoter. Overall, our work gives a molecular insight into ERα signalling and highlights a fundamental role of E2 in controlling human Treg cell physiology.
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Affiliation(s)
- Sreenivas Adurthi
- Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - Mahesh M Kumar
- Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - H S Vinodkumar
- Shodhaka Life Sciences Private Limited, Bangalore, India
- Structural Biology Lab, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Geetashree Mukherjee
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
- Department of Histopathology, Tata Medical Center, Kolkata, India
| | - H Krishnamurthy
- National Center for Biological Sciences, TIFR, Bangalore, India
| | - K Kshitish Acharya
- Shodhaka Life Sciences Private Limited, Bangalore, India
- Institute of Bioinformatics And Applied Biotechnology, Bangalore, India
| | - U D Bafna
- Department of Gynecology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - Devi K Uma
- Department of Gynecology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - B Abhishekh
- Department of Immunohematology, Kidwai Memorial Institute of Oncology, Bangalore, India
- Department of Transfusion Medicine, JIPMER, Puducherry, India
| | - Sudhir Krishna
- National Center for Biological Sciences, TIFR, Bangalore, India
| | - A Parchure
- Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - Murali Alka
- Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - R S Jayshree
- Department of Microbiology, Kidwai Memorial Institute of Oncology, Bangalore, India.
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Kumar MM, Davuluri S, Poojar S, Mukherjee G, Bajpai AK, Bafna UD, Devi UK, Kallur PPR, Kshitish AK, Jayshree RS. Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study. Tumour Biol 2015; 37:4409-20. [DOI: 10.1007/s13277-015-4257-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 10/15/2015] [Indexed: 11/30/2022] Open
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Phaëton R, Gutierrez J, Jiang Z, Karabakhtsian RG, Albanese J, Sunkara J, Fisher DR, Goldberg GL, Dadachova E. Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer. Immunotherapy 2015; 7:631-40. [PMID: 26098137 PMCID: PMC4524293 DOI: 10.2217/imt.15.18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. MATERIALS & METHODS We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific (188)Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. RESULTS The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. CONCLUSION We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy.
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MESH Headings
- Animals
- Antibodies, Neoplasm/immunology
- Antibodies, Neoplasm/pharmacology
- Antibodies, Viral/immunology
- Antibodies, Viral/pharmacology
- Female
- Human papillomavirus 16/immunology
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/radiotherapy
- Neoplasms, Experimental/virology
- Oncogene Proteins, Viral/immunology
- Papillomavirus E7 Proteins/immunology
- Papillomavirus Infections/immunology
- Papillomavirus Infections/therapy
- Radioimmunotherapy
- Repressor Proteins/immunology
- Uterine Cervical Neoplasms/immunology
- Uterine Cervical Neoplasms/radiotherapy
- Uterine Cervical Neoplasms/virology
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Affiliation(s)
- R Phaëton
- Department of Obstetrics & Gynecology, Albert Einstein College of Medicine, NY, USA
| | - J Gutierrez
- Department of Obstetrics & Gynecology, Albert Einstein College of Medicine, NY, USA
| | - Z Jiang
- Department of Radiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| | - RG Karabakhtsian
- Department of Pathology, Albert Einstein College of Medicine, NY, USA
| | - J Albanese
- Department of Pathology, Albert Einstein College of Medicine, NY, USA
| | - J Sunkara
- Department of Pathology, Albert Einstein College of Medicine, NY, USA
| | | | - GL Goldberg
- Department of Obstetrics & Gynecology, Albert Einstein College of Medicine, NY, USA
| | - E Dadachova
- Department of Radiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
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Song D, Li H, Li H, Dai J. Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer. Oncol Lett 2015; 10:600-606. [PMID: 26622540 DOI: 10.3892/ol.2015.3295] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 04/13/2015] [Indexed: 02/07/2023] Open
Abstract
Human papillomavirus (HPV) is widely known as a cause of cervical intraepithelial neoplasia (CIN) and cervical cancer. The mechanisms involved have been studied by numerous studies. The integration of the virus genome into the host cells results in the abnormal regulation of cell cycle control. HPV can also induce immune evasion of the infected cells, which enable the virus to be undetectable for long periods of time. The induction of immunotolerance of the host's immune system by the persistent infection of HPV is one of the most important mechanisms for cervical lesions. The present review elaborates on the roles of several types of immune cells, such as macrophages and natural killer cells, which are classified as innate immune cells, and dendritic cells (DCs), cluster of differentiation (CD)4+/CD8+ T cells and regulatory T cells, which are classified as adaptive immune cells. HPV infection could effect the differentiation of these immune cells in a unique way, resulting in the host's immune tolerance to the infection. The immune system modifications induced by HPV infection include tumor-associated macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T-helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and downregulated DC activation and maturation. To date, numerous types of preventative vaccines have been created to slow down carcinogenesis. Immune response activation-based therapeutic vaccine is becoming more and more attractive for the treatment of HPV-associated diseases.
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Affiliation(s)
- Dan Song
- Center for Reproduction and Genetics, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215002, P.R. China
| | - Hong Li
- Center for Reproduction and Genetics, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215002, P.R. China
| | - Haibo Li
- Center for Reproduction and Genetics, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215002, P.R. China
| | - Jianrong Dai
- Department of Gynecology, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215002, P.R. China
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Pathologic and imunohistochemical characterization of tumoral inflammatory cell infiltrate in invasive penile squamous cell carcinomas: Fox-P3 expression is an independent predictor of recurrence. Tumour Biol 2015; 36:2509-16. [PMID: 25557886 DOI: 10.1007/s13277-014-2864-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 11/17/2014] [Indexed: 10/24/2022] Open
Abstract
Penile carcinomas (PeCa) are relatively rare, but devastating neoplasms, more frequent among people of underprivileged socioeconomic status. There is mounting evidence that immune cells may trigger various mechanisms that enhance tumor growth and metastasis, but no data on the peritumoral inflammation is available for PeCa. The objectives of the present study are to evaluate the immunohistomorphology of tumoral inflammation in PeCa, and to correlate it with clinicopathological parameters, which could contribute to the prognostic evaluation. One hundred and twenty-two patients with the diagnosis of usual-type squamous cell penile carcinoma were included. Paraffin-embedded tissue was submitted to immunohistochemical evaluation of p16 protein, CD3, CD4, CD8, CD20, CD68, CD138, granzyme B, and Fox-P3. The Fisher's exact test was employed for comparison between histological variables and parameters, and the Kaplan-Meier method for the analysis of survival. Improved 5-year overall survival was significantly associated to age ≤60 years, stage I + II, tumor size T1 + T2, lymph node status N0, and absent perineural invasion. In a multivariate analysis age ≥60 years, presence of lymph node metastasis, urethral invasion, and high histologic grade retained a significantly more unfavorable outcome. Improved 5-year failure free survival was associated to stage of the disease I + II, lymph node status N0, absence of perineural, vascular, and urethral invasion, and Fox-P3 expression. In a multivariate analysis, presence of lymph node metastasis, perineural and vascular invasion, and of Fox-P3-positive lymphocytes together with low inflammatory infiltrate retained a significantly more unfavorable outcome. These results support the prognostic value of determining the levels of Fox-P3-positive lymphocytes by immunohistochemistry in PeCa, as this parameter adds value to the traditional clinicopathological features.
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Rath G, Jawanjal P, Salhan S, Nalliah M, Dhawan I. Clinical significance of inactivated glycogen synthase kinase 3β in HPV-associated cervical cancer: Relationship with Wnt/β-catenin pathway activation. Am J Reprod Immunol 2014; 73:460-78. [PMID: 25532422 DOI: 10.1111/aji.12346] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 11/18/2014] [Indexed: 11/29/2022] Open
Abstract
PROBLEM To determine the role of inactivated GSK3β with respect to Wnt/β-catenin pathway activation in HPV-16/18-associated cervical cancer. METHOD OF STUDY The expression of active (pGSK3β-Try(216)), inactive (pGSK3β-Ser(9)), and c-Myc as well as HPV-16/18 infection was analyzed in cervical intra-epithelial neoplasia (CIN), squamous cell carcinoma (SCCs) and normal by immunohistochemistry and multiplex PCR. The proteins level was also compared with β-catenin and APC expression. RESULTS The dramatic decrease of pGSK3β-Try(216) expression but ectopic overexpression of pGSK3β-Ser(9) and c-Myc was observed both in CIN and SCCs samples compared to normal tissues. 57/67 CIN and 132/153 SCCs showed HPV-16 infection, while 3/67 CIN and 4/153 SCCs were harbored with HPV-18 infection. Both the proteins were significantly upregulated in HPV-16 infected cases (P = 0.0001; P = 0.001) and also positively correlated with nuclear β-catenin (P = 0.0001; P = 0.0001). CONCLUSION The process of generation of HPV-16-associated cervical tumorigenesis is synergized with GSK3β inactivation and overactivation of Wnt/β-catenin pathway.
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Affiliation(s)
- Gayatri Rath
- Department of Anatomy, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
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Padovani CTJ, Bonin CM, Tozetti IA, Ferreira AMT, Fernandes CEDS, Costa IPD. Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection. Rev Soc Bras Med Trop 2013; 46:288-92. [DOI: 10.1590/0037-8682-0029-2013] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 06/04/2013] [Indexed: 11/22/2022] Open
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Functional tumor infiltrating TH1 and TH2 effectors in large early-stage cervical cancer are suppressed by regulatory T cells. Int J Gynecol Cancer 2013; 22:1130-7. [PMID: 22872166 DOI: 10.1097/igc.0b013e318262aa53] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Analysis of tumor-infiltrating lymphocytes (TILs) is one of the cornerstones for the understanding of immune responses prevailing in the tumor microenvironment. We studied TILs from squamous cell carcinoma of the cervix ex vivo without proliferating them in vitro before analysis. METHODS Whereas TILs were magnetic activated cell separation enriched and flow sorted into CD4 CD25 (regulatory T cells [Tregs]), CD4 CD25 (effector T cells [Teffs]) were directly purified by flow cytometry, and both these subsets were characterized phenotypically and functionally. Tissue sections were probed for interleukin 4 (IL-4) and interferon γ. RESULTS Effector T cells constitutively expressed both interferon γ and IL-4 prototypical cytokines of TH1 and TH2, respectively, and were able to proliferate and secrete higher quantities of both cytokines in response to anti-CD3/anti-CD28 and autologous tumor lysates. Only 53% of cervical cancer Tregs were FOXP3, elaborated transforming growth factor β1, and IL-10 and were able to inhibit both T helper subsets. CONCLUSIONS Intratumoral Teffs represented functionally active subsets of both TH1 and TH2 that were not anergic but were suppressed by multiple Treg subsets, which comprised FOXP3 + Tregs and Tregs secreting transforming growth factor β1 and IL-10. These results imply that the microenvironment of cervical carcinomas harbored both TH1 and TH2 subsets of CD4 Teffs that were functionally active but were perhaps unable to perform because of the overpowering effect of Tregs.
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Grabowska AK, Riemer AB. The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. Open Virol J 2012; 6:249-56. [PMID: 23341860 PMCID: PMC3547646 DOI: 10.2174/1874357901206010249] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 06/06/2012] [Accepted: 06/15/2012] [Indexed: 12/20/2022] Open
Abstract
Human papillomavirus (HPV) needs to persist in squamous epithelia for a certain amount of time to complete its reproductive cycle. Therefore, the virus has evolved multiple immune evasion strategies. The interplay of these immune evasion mechanisms with the host immune system decides whether a HPV infection is cleared or becomes persistent. Clearance of HPV-induced lesions is mediated by a cellular immune response, consisting of both cytotoxic T lymphocyte and T helper cell responses. Persistent HPV infection, on the other hand, is the single most important risk factor for the development of HPV-associated premalignant lesions and HPV-driven cancers. This article reviews the immune evasion mechanisms employed by high-risk HPVs to escape host immune recognition and attack.
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Affiliation(s)
- Agnieszka K Grabowska
- Immunotherapy and -prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany
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39
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Lm-LLO-Based Immunotherapies and HPV-Associated Disease. JOURNAL OF ONCOLOGY 2012; 2012:542851. [PMID: 22481930 PMCID: PMC3307007 DOI: 10.1155/2012/542851] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Accepted: 10/09/2011] [Indexed: 01/06/2023]
Abstract
HPV infection is a direct cause of neoplasia and malignancy. Cellular immunologic activity against cells expressing HPV E6 and E7 is sufficient to eliminate the presence of dysplastic or neoplastic tissue driven by HPV infection. Live attenuated Listeria monocytogenes- (Lm-) based immunotherapy (ADXS11-001) has been developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7. In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome. ADXS11-001 is currently being evaluated in Phase 2 clinical trials for cervical intraepithelial neoplasia, cervical cancer, and HPV-positive head and neck cancer. The use of a live attenuated bacterium is a more complex and complete method of cancer immunotherapy, as over millennia Lm has evolved to infect humans and humans have evolved to prevent and reject this infection over millennia. This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.
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Bedoya AM, Jaramillo R, Baena A, Castaño J, Olaya N, Zea AH, Herrero R, Sanchez GI. Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer. CANCER MICROENVIRONMENT 2012; 6:69-77. [PMID: 22290207 DOI: 10.1007/s12307-012-0097-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Accepted: 01/11/2012] [Indexed: 12/21/2022]
Abstract
Only a small proportion of women infected with Human Papillomavirus (HPV) develop cervical cancer. Host immune response seems to play a role eliminating the viral infection and preventing progression to cancer. Characterization of tumor infiltrating lymphocytes (TILs) in cervical pre-neoplastic lesions and cervical cancer may be helpful to understand the mechanisms that mediate this protection. The aim of this study was to determine if there are differences in the localization and density (cells/mm(2)) of CD8+ T-cells, CD4+ T-cells and Tregs (CD25 + Foxp3+) in cervical pre-neoplastic lesions and cervical cancer. Immunohistochemical analysis of sections of 96 (26 CIN1, 21 CIN2, 25 CIN3, and 24 SCC) samples revealed that regardless of CIN grades, CD8+ T-cells are more abundant than CD4+, CD25+ and Foxp3+ cells in both the stroma and epithelium. There was a higher density of CD8+ cells in the stroma of cervical cancer compared to CIN3 (OR = 4.20, 95% CI 1.2-15), CIN2 (OR = 7.86, 95% CI 1.7-36.4) and CIN1 (OR = 4.25, 95% CI 1.1-17). Studies evaluating whether these cells are recruited before or after cancer progression will be helpful to understand the role of these cells in the natural history of HPV-induced lesions.
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Affiliation(s)
- Astrid M Bedoya
- Grupo Infección y Cáncer, Facultad de Medicina, Universidad de Antioquia, Cra 51D No. 62-29 Lab 283, Medellin, Colombia
- Escuela de Microbiología, Universidad de Antioquia, Medellin, Colombia
| | | | - Armando Baena
- Grupo Infección y Cáncer, Facultad de Medicina, Universidad de Antioquia, Cra 51D No. 62-29 Lab 283, Medellin, Colombia
- Escuela de Microbiología, Universidad de Antioquia, Medellin, Colombia
| | - Jorge Castaño
- Departamento de Patología, Facultad de Medicina, Universidad de Antioquia and Hospital Universitario San Vicente de Paúl, Medellin, Colombia
| | - Natalia Olaya
- Departamento de Patología, Facultad de Medicina, Universidad de Antioquia and Hospital Universitario San Vicente de Paúl, Medellin, Colombia
| | - Arnold H Zea
- Department of Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Rolando Herrero
- Prevention and Implementation Group, International Agency for Research on Cancer, Lyon, France
| | - Gloria I Sanchez
- Grupo Infección y Cáncer, Facultad de Medicina, Universidad de Antioquia, Cra 51D No. 62-29 Lab 283, Medellin, Colombia.
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Cheng HH, Tseng GY, Yang HB, Wang HJ, Lin HJ, Wang WC. Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma. World J Gastroenterol 2012; 18:34-43. [PMID: 22228968 PMCID: PMC3251803 DOI: 10.3748/wjg.v18.i1.34] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 06/20/2011] [Accepted: 06/27/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis, peptic ulcers and gastric cancer.
METHODS: This study was a retrospective analysis of gastric antrum biopsy specimens from healthy controls (n = 22) and patients with gastritis (n = 30), peptic ulcer (n = 83), or gastric cancer (n = 32). Expression of CD4, CD25 and Foxp3 was determined by immunohistochemistry in three consecutive sections per sample.
RESULTS: Compared with healthy controls, there was an increased number of CD25+ and Foxp3+ cells in patients with gastritis (P = 0.004 and P = 0.008), peptic ulcer (P < 0.001 and P < 0.001), and gastric cancer (P < 0.001 and P < 0.001). The ratio of CD25+/CD4+ or Foxp3+/CD4+ cells was also significantly higher in all disease groups (P < 0.001, respectively). The number of CD4+, CD25+, and Foxp3+ cells, and the ratio of CD25+/CD4+ and Foxp3+/CD4+ cells, were associated with the histological grade of the specimens, including acute inflammation, chronic inflammation, lymphoid follicle number, and Helicobacter pylori infection. The number of CD4+, CD25+ and Foxp3+ cells, and the ratio of CD25+/CD4+ and Foxp3+/CD4+ cells, were negatively associated with intestinal metaplasia among gastritis (P < 0.001, P < 0.001, P < 0.001, P = 0.002 and P = 0.002) and peptic ulcer groups (P = 0.013, P = 0.004, P < 0.001, P = 0.040 and P = 0.003).
CONCLUSION: Tregs are positively associated with endoscopic findings of gastroduodenal diseases and histological grade but negatively associated with intestinal metaplasia in gastritis and peptic ulcer groups.
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Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines. Med Hypotheses 2011; 77:777-81. [PMID: 21840649 DOI: 10.1016/j.mehy.2011.07.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 07/16/2011] [Indexed: 11/21/2022]
Abstract
There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity), to prolong its own survival (balance with the virus), to avoid the risk of producing uncontrolled cells (dangerous outcomes). Finally, the postulated negative implications for therapeutic vaccines in cervical cancer, as they really seem to not work till now might be ascribed just to the cited host immune-specific state itself, through an activation induced cell death, elicited by recall antigens (E6/E7 in the case of my wife). Also this latter hypothesis, as well as the previous ones may be of some value to better account for clinical behaviors and researches.
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Matijevic M, Hedley ML, Urban RG, Chicz RM, Lajoie C, Luby TM. Immunization with a poly (lactide co-glycolide) encapsulated plasmid DNA expressing antigenic regions of HPV 16 and 18 results in an increase in the precursor frequency of T cells that respond to epitopes from HPV 16, 18, 6 and 11. Cell Immunol 2011; 270:62-9. [PMID: 21550027 PMCID: PMC7094646 DOI: 10.1016/j.cellimm.2011.04.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Revised: 03/24/2011] [Accepted: 04/14/2011] [Indexed: 01/08/2023]
Abstract
A phase II trial was conducted in subjects with human papillomavirus (HPV) associated high-grade cervical dysplasia testing the safety and efficacy of a microparticle encapsulated pDNA vaccine. Amolimogene expresses T cell epitopes from E6 and E7 proteins of HPV types 16 and 18. An analysis was performed on a subset of HLA-A2+ subjects to test whether CD8+ T cells specific to HPV 16, 18, 6 and 11 were increased in response to amolimogene immunization. Of the 21 subjects receiving amolimogene, 11 had elevated CD8+ T cell responses to HPV 16 and/or 18 peptides and seven of these also had increases to corresponding HPV 6 and/or 11 peptides. In addition, T cells primed and expanded in vitro with an HPV 18 peptide demonstrated cross-reactivity to the corresponding HPV 11 peptide. These data demonstrate that treatment with amolimogene elicits T cell responses to HPV 16, 18, 6 and 11.
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Gu Y, Wang C, Han D, Zhang L. Increased frequencies of CD4+ CD25+ FOXP3+ regulatory T cells in human nasal inverted papilloma. Head Neck 2010; 33:1005-12. [PMID: 21674673 DOI: 10.1002/hed.21581] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2010] [Revised: 06/08/2010] [Accepted: 07/09/2010] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The purpose of this study was to investigate the presence of CD4(+) CD25(+) FOXP3(+) regulatory T (Treg) cells both in peripheral blood and local tumors in patients with nasal inverted papilloma (NIP). METHODS By using flow cytometry, the frequencies of CD4(+) CD25(+) FOXP3(+) Treg cells in both peripheral blood and tissues from 18 patients with NIP and 8 control subjects were determined. CCL22 and CCL17 proteins in NIP tumors were analyzed by using enzyme-linked immunosorbent assay. The suppressive capacity of Treg cells was estimated by WST-8 and enzyme-linked immunosorbent assay (ELISA; interferon-gamma [IFN-γ] and interleukin-4 [IL-4]) analysis. RESULTS Patients with NIP showed increased CD4(+) CD25(+) FOXP3(+) Treg cell frequencies in tumor tissues and CD4(+) T cell fraction rather than in peripheral blood. CCL22 increased in NIP tumors. Phytohemagglutinin (PHA)-induced proliferation and cytokine production of CD4(+) CD25(-) T cells were suppressed equally well by CD4(+) CD25(high) cells from both patients with NIP and controls. CONCLUSION Our study demonstrated the increased frequencies of CD4(+) CD25(+) FOXP3(+) Treg cells in NIP tumors, which might be influenced by CCL22.
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Affiliation(s)
- Yili Gu
- Key Laboratory of Otolaryngology-Head and Neck Surgery, Capital Medical University, Ministry of Education of China, Beijing Institute of Otorhinolaryngology, Beijing 100005, China
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de Souza AP, Bonorino C. Tumor immunosuppressive environment: effects on tumor-specific and nontumor antigen immune responses. Expert Rev Anticancer Ther 2009; 9:1317-32. [PMID: 19761435 DOI: 10.1586/era.09.88] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The interactions between cancer cells and host immune cells in tumoral microenvironments create an immunosuppressive network that promotes tumor growth, protects the tumor from immune attack and attenuates the efficacy of immunotherapeutic approaches. The development of immune tolerance becomes predominant in the immune system of patients with advanced-stage tumors. Several mechanisms have been described by which tumors can suppress the immune system, including secretion of cytokines, alterations in antigen-presenting cell subsets, costimulatory and coinhibitory molecule alterations and altered ratios of Tregs to effector T cells. It is well demonstrated that these mechanisms of immunosuppression can impair tumor specific immune responses. However, it is not well established whether this immunosuppressive environment can affect immune responses to nontumor antigens, specifically in regard to priming and the development of memory. The few existing studies indicate that responses to nontumor antigens seem unaffected, although there is still a deep lack of understanding of this phenomenon. This is an important issue regarding patient endurance and quality of life. Here, we review the existing evidence on immunosuppression promoted by tumors, with particular attention to its impact on specific immune responses. Understanding these interactions can help us subvert tumor-induced tolerance and optimize anti-tumor therapy.
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Affiliation(s)
- Ana Paula de Souza
- Departamento de Biologia Celular e Molecular (FABIO) and Instituto de Pesquisas Biomédicas, PUCRS. Av. Ipiranga, 6690 2o andar; 90610-90000 Porto Alegre, RS, Brazil.
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Frazer IH. Interaction of human papillomaviruses with the host immune system: a well evolved relationship. Virology 2008; 384:410-4. [PMID: 18986661 DOI: 10.1016/j.virol.2008.10.004] [Citation(s) in RCA: 128] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Accepted: 10/03/2008] [Indexed: 12/22/2022]
Abstract
Human papillomavirus (HPV) infections are generally long lasting, and a host immune response to infection is hard to detect. Nevertheless immunocompromised subjects control HPV infection less well than those with intact immunity. Immune responses are best documented for the papillomavirus groups that cause evident human disease, particularly those responsible for anogenital cancers and genital warts. Humoral immunity to the viral capsid has been shown sufficient for protection against infection, while innate and adaptive cell mediated immunity appears important for eventual elimination of HPV infection. However, molecular and cellular mechanisms responsible for protection from and clearance of HPV infection are not completely established.
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Affiliation(s)
- Ian H Frazer
- The University of Queensland Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia.
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