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1
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Li J, Zhou M, Xie J, Chen J, Yang M, Ye C, Cheng S, Liu M, Li R, Tan R. Organoid modeling meets cancers of female reproductive tract. Cell Death Discov 2024; 10:410. [PMID: 39333482 PMCID: PMC11437045 DOI: 10.1038/s41420-024-02186-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 08/13/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024] Open
Abstract
Diseases of the female reproductive system, especially malignant tumors, pose a serious threat to women's health worldwide. One of the key factors limiting research progress in this area is the lack of representative models. Organoid technology, especially tumor organoids, has been increasingly applied in the study of female reproductive system tumors due to their high heterogeneity, close resemblance to the physiological state, easy acquisition and cultivation advantages. They play a significant role in understanding the origin and causes of tumors, drug screening, and personalized treatment and more. This article reviews the organoid models for the female reproductive system, focusing on the cancer research advancements. It discusses the methods for constructing tumor organoids of the female reproductive tract and summarizes the limitations of current research. The aim is to offer a reference for future development and application of these organoid models, contributing to the advancement of anti-tumor drugs and treatment strategies for female reproductive tract cancer patients.
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Affiliation(s)
- Jiao Li
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Mengting Zhou
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jun Xie
- Information Technology Center, West China Hospital of Sichuan University, Sichuan University, Chengdu, China
| | - Jiani Chen
- Chongqing Medical University, Chongqing, China
| | - Mengni Yang
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Changjun Ye
- Rehabilitation Department, Changgeng Yining Hospital, Wenzhou, China
| | - Shihu Cheng
- Geriatric Department, Changgeng Yining Hospital, Wenzhou, China
| | - Miao Liu
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Rui Li
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
| | - Ruirong Tan
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, China.
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Jain M, Yadav D, Jarouliya U, Chavda V, Yadav AK, Chaurasia B, Song M. Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis. Pathogens 2023; 12:1380. [PMID: 38133265 PMCID: PMC10745624 DOI: 10.3390/pathogens12121380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/08/2023] [Accepted: 11/20/2023] [Indexed: 12/23/2023] Open
Abstract
Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. HPV-16 and -18 are mainly responsible for the progression of several cancers, including cervix, anus, vagina, penis, vulva, and oropharynx. The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment. Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. In addition, vaccination awareness programs and preventive strategies could help reduce the rate and incidence of HPV infection. In this review, we emphasize HPV infection and its role in cancer progression, molecular and immunopathogenesis, host immune response, immune evasion by HPV, vaccination, and preventive schemes battling HPV infection and HPV-related cancers.
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Affiliation(s)
- Meenu Jain
- Department of Microbiology, Viral Research and Diagnostic Laboratory, Gajra Raja Medical College, Gwalior 474009, Madhya Pradesh, India
| | - Dhananjay Yadav
- Department of Life Science, Yeungnam University, Gyeongsan 38541, Republic of Korea;
| | - Urmila Jarouliya
- SOS in Biochemistry, Jiwaji University, Gwalior 474011 Madhya Pradesh, India;
| | - Vishal Chavda
- Department of Pathology, Stanford School of Medicine, Stanford University Medical Center, Palo Alto, CA 94305, USA;
| | - Arun Kumar Yadav
- Department of Microbiology, Guru Gobind Singh Medical College and Hospital, Baba Farid University of Health Sciences, Faridkot 151203, Punjab, India;
| | - Bipin Chaurasia
- Department of Neurosurgery, Neurosurgery Clinic, Birgunj 44300, Nepal;
| | - Minseok Song
- Department of Life Science, Yeungnam University, Gyeongsan 38541, Republic of Korea;
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Condrat CE, Cretoiu D, Radoi VE, Mihele DM, Tovaru M, Bordea CI, Voinea SC, Suciu N. Unraveling Immunological Dynamics: HPV Infection in Women-Insights from Pregnancy. Viruses 2023; 15:2011. [PMID: 37896788 PMCID: PMC10611104 DOI: 10.3390/v15102011] [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: 08/19/2023] [Revised: 09/23/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023] Open
Abstract
During pregnancy, hormonal and immune adaptations are vital for supporting the genetically distinct fetus during elevated infection risks. The global prevalence of HPV necessitates its consideration during pregnancy. Despite a seemingly mild immune response, historical gestational viral infections underscore its significance. Acknowledging the established HPV infection risks during pregnancy, our review explores the unfolding immunological changes in pregnant women with HPV. Our analysis aims to uncover strategies for safely modulating the immune system, mitigating adverse pregnancy consequences, and enhancing maternal and child health. This comprehensive narrative review delves into the existing knowledge and studies on this topic.
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Affiliation(s)
- Carmen Elena Condrat
- Department of Obstetrics and Gynecology, Polizu Clinical Hospital, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania; (C.E.C.)
| | - Dragos Cretoiu
- Department of Genetics, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania; (D.C.); (V.E.R.)
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
| | - Viorica Elena Radoi
- Department of Genetics, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania; (D.C.); (V.E.R.)
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
| | - Dana Mihaela Mihele
- Department of Dermatology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Mihaela Tovaru
- Department of Dermatology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Cristian Ioan Bordea
- Department of Surgical Oncology, Prof. Dr. Alexandru Trestioreanu Oncology Institute, Carol Davila University of Medicine and Pharmacy, 252 Fundeni Rd., 022328 Bucharest, Romania
| | - Silviu Cristian Voinea
- Department of Surgical Oncology, Prof. Dr. Alexandru Trestioreanu Oncology Institute, Carol Davila University of Medicine and Pharmacy, 252 Fundeni Rd., 022328 Bucharest, Romania
| | - Nicolae Suciu
- Department of Obstetrics and Gynecology, Polizu Clinical Hospital, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd., 050474 Bucharest, Romania; (C.E.C.)
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
- Department of Obstetrics and Gynecology, Polizu Clinical Hospital, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
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Zhao C, Yan S, Song Y, Xia X. Roles of Antimicrobial Peptides in Gynecological Cancers. Int J Mol Sci 2022; 23:ijms231710104. [PMID: 36077500 PMCID: PMC9456504 DOI: 10.3390/ijms231710104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 12/29/2022] Open
Abstract
Antimicrobial peptides (AMPs) are essential components of the mucosal barrier of the female reproductive tract (FRT) and are involved in many important physiological processes, including shaping the microbiota and maintaining normal reproduction and pregnancy. Gynecological cancers seriously threaten women's health and bring a heavy burden to society so that new strategies are needed to deal with these diseases. Recent studies have suggested that AMPs also have a complex yet intriguing relationship with gynecological cancers. The expression level of AMPs changes during tumor progression and they may act as promising biomarkers in cancer detection and prognosis prediction. Although AMPs have long been considered as host protective, they actually play a "double-edged sword" role in gynecological cancers, either tumorigenic or antitumor, depending on factors such as AMP and cancer types, as well as AMP concentrations. Moreover, AMPs are associated with chemoresistance and regulation of AMPs' expression may alter sensitivity of cancer cells to chemotherapy. However, more work is needed, especially on the identification of molecular mechanisms of AMPs in the FRT, as well as the clinical application of these AMPs in detection, diagnosis and treatment of gynecological malignancies.
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5
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Muñoz-Mata LS, López-Cárdenas MT, Espinosa-Montesinos A, Sosa-Delgado SM, Rosales-García VH, Moreno-Lafont MC, Ramón-Gallegos E. Photodynamic therapy stimulates IL-6 and IL-8 in responding patients with HPV infection associated or not with LSIL. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY 2022. [DOI: 10.1016/j.jpap.2022.100137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Ojha PS, Maste MM, Tubachi S, Patil VS. Human papillomavirus and cervical cancer: an insight highlighting pathogenesis and targeting strategies. Virusdisease 2022; 33:132-154. [DOI: 10.1007/s13337-022-00768-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 05/07/2022] [Indexed: 11/29/2022] Open
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7
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Fernandes ATG, Carvalho MOO, Avvad-Portari E, Rocha NP, Russomano F, Roma EH, Bonecini-Almeida MDG. A prognostic value of CD45RA +, CD45RO +, CCL20 + and CCR6 + expressing cells as 'immunoscore' to predict cervical cancer induced by HPV. Sci Rep 2021; 11:8782. [PMID: 33888832 PMCID: PMC8062468 DOI: 10.1038/s41598-021-88248-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 04/01/2021] [Indexed: 02/06/2023] Open
Abstract
The interplay between cervical cancer (CC) and immune cells, mainly intratumoral lymphocytes, has a pivotal role in carcinogenesis. In this context, we evaluated the distribution of CD45RA+ and CD45RO+ cells as well as CCR6+ and CCL20+ cells in intraepithelial (IE) and marginal stroma (MS) areas from cervical intraepithelial neoplasia (CIN) I-III, and CC as 'immunoscore' for HPV-induced CC outcome. We observed increased CD45RA+ and CD45RO+ cells distribution in IE and MS areas in the CC group compared to CIN groups and healthy volunteers. Interestingly, there is a remarkable reduction of CCL20+ expressing cells distribution according to lesion severity. The CC group had a significant decrease in CCL20+ and CCR6+-expressing cells distribution in both IE and MS areas compared to all groups. Using the 'immunoscore' model, we observed an increased number of women presenting high CD45RA+/CD45RO+ and low CCL20+/CCR6+ 'immunoscore' in the CC group. Our results suggested a pattern in cervical inflammatory process with increasing CD45RA+/CD45RO+, and decreasing CCL20+/CCR6+ expression in accordance with CIN severity. Taken together, these markers could be evaluated as 'immunoscore' predictors to CC response. A more comprehensive analysis of longitudinal studies should be conducted to associate CD45RA+/CD45RO+ and CCL20+/CCR6+ 'immunoscore' to CC progression and validate its value as a prognosis method.
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Affiliation(s)
- Ana Teresa G Fernandes
- Laboratory of Immunology and Immunogenetics in Infectious Diseases at Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Rio de Janeiro, RJ, 21040-900, Brazil.
| | - Maria Odete O Carvalho
- Laboratory of Immunology and Immunogenetics in Infectious Diseases at Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Rio de Janeiro, RJ, 21040-900, Brazil
| | - Elyzabeth Avvad-Portari
- Department of Pathologic Anatomy at Fernandes Figueira Woman, Child and Adolescent's Health National Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Natália P Rocha
- Laboratory of Immunology and Immunogenetics in Infectious Diseases at Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Rio de Janeiro, RJ, 21040-900, Brazil
| | - Fabio Russomano
- Department of Gynecology at Fernandes Figueira Woman, Child and Adolescent's Health National Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Eric Henrique Roma
- Laboratory of Immunology and Immunogenetics in Infectious Diseases at Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Rio de Janeiro, RJ, 21040-900, Brazil
| | - Maria da Gloria Bonecini-Almeida
- Laboratory of Immunology and Immunogenetics in Infectious Diseases at Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365, Rio de Janeiro, RJ, 21040-900, Brazil
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8
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Deng H, Hillpot E, Mondal S, Khurana KK, Woodworth CD. HPV16-Immortalized Cells from Human Transformation Zone and Endocervix are More Dysplastic than Ectocervical Cells in Organotypic Culture. Sci Rep 2018; 8:15402. [PMID: 30337615 PMCID: PMC6194146 DOI: 10.1038/s41598-018-33865-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 10/03/2018] [Indexed: 12/28/2022] Open
Abstract
A major risk factor for cervical cancer is persistent infection with high-risk human papillomaviruses (HPV) which can cause cervical intraepithelial neoplasia. Greater than 90% of cervical cancers develop in the transformation zone (TZ), a small region of metaplastic squamous epithelium at the squamocolumnar junction between endocervix and ectocervix. However, it is unclear why this region is highly susceptible to malignant progression. We hypothesized that cells from TZ were more susceptible to dysplastic differentiation, a precursor to cervical cancer. We used three-dimensional organotypic culture to compare differentiation of HPV16-immortalized epithelial cell lines derived from ectocervix, TZ, and endocervix. We show that immortal cells from TZ or endocervix form epithelia that are more dysplastic than immortal cells from ectocervix. A higher percentage of immortal cells from TZ and endocervix express the proliferation marker Ki-67 and are positive for phospho-Akt. Immortal cells from TZ and endocervix invade collagen rafts and express increased levels of matrix metalloproteinase-1. Inhibition of MMP-1 or Akt activity blocks invasion. We conclude that HPV16-immortalized cells cultured from TZ or endocervix are more susceptible to dysplastic differentiation, and this might enhance their susceptibility to cervical cancer.
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Affiliation(s)
- Han Deng
- Department of Biology, Clarkson University, Potsdam, NY, United States of America
| | - Eric Hillpot
- Department of Biology, Clarkson University, Potsdam, NY, United States of America
| | - Sumona Mondal
- Department of Mathematics, Clarkson University, Potsdam, NY, United States of America
| | - Kamal K Khurana
- Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Craig D Woodworth
- Department of Biology, Clarkson University, Potsdam, NY, United States of America.
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9
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Susceptibility of epithelial cells cultured from different regions of human cervix to HPV16-induced immortalization. PLoS One 2018; 13:e0199761. [PMID: 29944714 PMCID: PMC6019754 DOI: 10.1371/journal.pone.0199761] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 06/13/2018] [Indexed: 12/24/2022] Open
Abstract
Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for cervical cancer. Greater than 90% of these cancers originate in the cervical transformation zone (TZ), a narrow region of metaplastic squamous epithelium that develops at the squamocolumnar junction between the ectocervix and endocervix. It is unclear why the TZ has high susceptibility to malignant transformation and few studies have specifically examined cells from this region. We hypothesized that cells cultured from TZ are more susceptible to cellular immortalization, an alteration that contributes to malignant development. We cultured primary epithelial cells from each region of human cervix (ectocervix, endocervix and TZ) and measured susceptibility to immortalization after transfection with the complete HPV-16 genome or infection of HPV16 E6/E7 retroviruses. Cells cultured from each cervical region expressed keratin markers (keratin 14 and 18) that confirmed their region of origin. In contrast to our prediction, cells from TZ were equally susceptible to immortalization as cells from ectocervix or endocervix. Thus, increased susceptibility of the TZ to cervical carcinogenesis is not due to increased frequency of immortalization by HPV-16. We developed a series of HPV16-immortalized cell lines from ectocervix, endocervix and TZ that will enable comparisons of how these cells respond to factors that promote cervical carcinogenesis.
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10
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High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis. Int J Mol Sci 2018; 19:ijms19061706. [PMID: 29890655 PMCID: PMC6032416 DOI: 10.3390/ijms19061706] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/13/2022] Open
Abstract
Infection with high-risk human papillomavirus (HPV) has been linked to several human cancers, the most prominent of which is cervical cancer. The integration of the viral genome into the host genome is one of the manners in which the viral oncogenes E6 and E7 achieve persistent expression. The most well-studied cellular targets of the viral oncogenes E6 and E7 are p53 and pRb, respectively. However, recent research has demonstrated the ability of these two viral factors to target many more cellular factors, including proteins which regulate epigenetic marks and splicing changes in the cell. These have the ability to exert a global change, which eventually culminates to uncontrolled proliferation and carcinogenesis.
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11
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Da Silva DM, Woodham AW, Skeate JG, Rijkee LK, Taylor JR, Brand HE, Muderspach LI, Roman LD, Yessaian AA, Pham HQ, Matsuo K, Lin YG, McKee GM, Salazar AM, Kast WM. Langerhans cells from women with cervical precancerous lesions become functionally responsive against human papillomavirus after activation with stabilized Poly-I:C. Clin Immunol 2015; 161:197-208. [PMID: 26360252 DOI: 10.1016/j.clim.2015.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Revised: 08/27/2015] [Accepted: 09/01/2015] [Indexed: 12/15/2022]
Abstract
Human papillomavirus (HPV)-mediated suppression of Langerhans cell (LC) function can lead to persistent infection and development of cervical intraepithelial neoplasia (CIN). Women with HPV-induced high-grade CIN2/3 have not mounted an effective immune response against HPV, yet it is unknown if LC-mediated T cell activation from such women is functionally impaired against HPV. We investigated the functional activation of in vitro generated LC and their ability to induce HPV16-specific T cells from CIN2/3 patients after exposure to HPV16 followed by treatment with stabilized Poly-I:C (s-Poly-I:C). LC from patients exposed to HPV16 demonstrated a lack of costimulatory molecule expression, inflammatory cytokine secretion, and chemokine-directed migration. Conversely, s-Poly-I:C caused significant phenotypic and functional activation of HPV16-exposed LC, which resulted in de novo generation of HPV16-specific CD8(+) T cells. Our results highlight that LC of women with a history of persistent HPV infection can present HPV antigens and are capable of inducing an adaptive T cell immune response when given the proper stimulus, suggesting that s-Poly-I:C compounds may be attractive immunomodulators for LC-mediated clearance of persistent HPV infection.
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Affiliation(s)
- Diane M Da Silva
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA.
| | - Andrew W Woodham
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA
| | - Joseph G Skeate
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Laurie K Rijkee
- Groningen International Program of Science in Medicine, University of Groningen, Groningen, The Netherlands
| | - Julia R Taylor
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA
| | - Heike E Brand
- Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA
| | - Laila I Muderspach
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Lynda D Roman
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Annie A Yessaian
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Huyen Q Pham
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Koji Matsuo
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA
| | - Yvonne G Lin
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA
| | | | | | - W Martin Kast
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, USA; Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA, USA
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12
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Prata TTM, Bonin CM, Ferreira AMT, Padovani CTJ, Fernandes CEDS, Machado AP, Tozetti IA. Local immunosuppression induced by high viral load of human papillomavirus: characterization of cellular phenotypes producing interleukin-10 in cervical neoplastic lesions. Immunology 2015; 146:113-21. [PMID: 26059395 DOI: 10.1111/imm.12487] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 05/27/2015] [Accepted: 05/29/2015] [Indexed: 12/17/2022] Open
Abstract
A specific immune response to human papillomavirus (HPV) in the cervical microenvironment plays a key role in eradicating infection and eliminating mutated cells. However, high-risk HPVs modulate immune cells to create an immunosuppressive microenvironment, and induce these immune cells to produce interleukin 10 (IL-10). This production of IL-10, in conjunction with HPV infection, contributes to the appearance of cervical neoplastic lesions. We sought to characterize the IL-10-producing cellular phenotype, and investigate the influence of host and HPV factors upon the induction of an immunosuppressive microenvironment. Immunohistochemical analysis demonstrated an increase in IL-10 production by keratinocytes, macrophages and Langerhans cells in high-grade cervical lesions and cervical cancer. This increase was more pronounced in patients older than 30 years, and was also correlated with high viral load, and infection with a single HPV type, particularly high-risk HPVs. Our results indicate the existence of a highly immunosuppressive microenvironment composed of different IL-10-producing cellular phenotypes in cervical cancer samples, and samples classified as high-grade cervical lesions (cervical intraepithelial neoplasia stages II and III). The immunosuppressive microenvironment that developed for these different cellular phenotypes favours viral persistence and neoplastic progression.
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Affiliation(s)
- Thiago Theodoro Martins Prata
- Postgraduate Programme of Infectious and Parasitic Diseases, School of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, Brazil
| | - Camila Mareti Bonin
- Centre for Biological and Health Sciences, Federal University of Mato Grosso do Sul, Campo Grande, Brazil
| | | | | | | | - Ana Paula Machado
- Multicentre Postgraduate Programme in Biochemistry and Molecular Biology, Federal University of Mato Grosso do Sul, Campo Grande, Brazil
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13
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Demoulin SA, Somja J, Duray A, Guénin S, Roncarati P, Delvenne PO, Herfs MF, Hubert PM. Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion. Oncoimmunology 2015; 4:e1008334. [PMID: 26155412 PMCID: PMC4485731 DOI: 10.1080/2162402x.2015.1008334] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 12/16/2014] [Accepted: 01/08/2015] [Indexed: 12/20/2022] Open
Abstract
The progression of genital human papillomavirus (HPV) infections into preneoplastic lesions suggests that infected/malignant cells are not adequately recognized by the immune system. In this study, we demonstrated that cervical/vulvar cancer cells secrete factor(s) that affect both the maturation and function of dendritic cells (DC) leading to a tolerogenic profile. Indeed, DC cocultured with cancer cell lines display both a partially mature phenotype after lipopolysaccharide (LPS) maturation and an altered secretory profile (IL-10high and IL-12p70low). In addition, tumor-converted DC acquire the ability to alter T-cell proliferation and to induce FoxP3+ suppressive T cells from naive CD4+ T cells. Among the immunosuppressive factors implicated in DC alterations in genital (pre)neoplastic microenvironment, we identified receptor activator of nuclear factor kappa-B ligand (RANKL), a TNF family member, as a potential candidate. For the first time, we showed that RANKL expression strongly increases during cervical progression. We also confirmed that RANKL is directly secreted by cancer cells and this expression is not related to HPV viral oncoprotein induction. Interestingly, the addition of osteoprotegerin (OPG) in coculture experiments reduces significantly the inhibition of DC maturation, the release of a tolerogenic cytokine profile (IL-12low IL-10high) and the induction of regulatory T (Treg) cells. Our findings suggest that the use of inhibitory molecules directed against RANKL in cervical/vulvar (pre)neoplastic lesions might prevent alterations of DC functionality and represent an attractive strategy to overcome immune tolerance in such cancers.
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Key Words
- LC, Langerhans cells; LPS, lipopolysaccharide
- APC, antigen presenting cells; DC, dendritic cells
- GILZ, glucocorticoid-induced leucine zipper; HPV, human papillomavirus
- HSIL, high grade intraepithelial lesions
- IHC, immunohistochemistry
- ILT3, Immunoglobulin-like transcript 3
- KN, normal keratinocytes
- LSIL, low grade intraepithelial lesion
- MFI, mean fluorescence intensity
- OPG, osteoprotegerin
- PBMC, peripheral blood mononuclear cells; pDC, plasmacytoid dendritic cells
- RANKL
- RANKL, Receptor activator of nuclear factor kappa-B ligand
- SCC, squamous cell carcinoma
- SIL, squamous intraepithelial neoplasia
- Treg cells
- Treg cells, regulatory T cells
- VIN, vulvar intraepithelial neoplasia
- cervical cancers
- dendritic cells
- tolerogenicity
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Affiliation(s)
- Stéphanie A Demoulin
- Laboratory of Experimental Pathology; GIGA-Cancer; University of Liège ; Liège, Belgium
| | - Joan Somja
- Department of Pathology; University Hospital of Liège ; Liège, Belgium
| | - Anaëlle Duray
- Laboratory of Experimental Pathology; GIGA-Cancer; University of Liège ; Liège, Belgium
| | - Samuel Guénin
- Laboratory of Experimental Pathology; GIGA-Cancer; University of Liège ; Liège, Belgium
| | - Patrick Roncarati
- Laboratory of Experimental Pathology; GIGA-Cancer; University of Liège ; Liège, Belgium
| | | | - Michael F Herfs
- Laboratory of Experimental Pathology; GIGA-Cancer; University of Liège ; Liège, Belgium
| | - Pascale M Hubert
- Laboratory of Experimental Pathology; GIGA-Cancer; University of Liège ; Liège, Belgium
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14
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Yarbrough VL, Winkle S, Herbst-Kralovetz MM. Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications. Hum Reprod Update 2014; 21:353-77. [PMID: 25547201 DOI: 10.1093/humupd/dmu065] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 12/10/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND At the interface of the external environment and the mucosal surface of the female reproductive tract (FRT) lies a first-line defense against pathogen invasion that includes antimicrobial peptides (AMP). Comprised of a unique class of multifunctional, amphipathic molecules, AMP employ a wide range of functions to limit microbial invasion and replication within host cells as well as independently modulate the immune system, dampen inflammation and maintain tissue homeostasis. The role of AMP in barrier defense at the level of the skin and gut has received much attention as of late. Given the far reaching implications for women's health, maternal and fetal morbidity and mortality, and sexually transmissible and polymicrobial diseases, we herein review the distribution and function of key AMP throughout the female reproductive mucosa and assess their role as an essential immunological barrier to microbial invasion throughout the reproductive cycle of a woman's lifetime. METHODS A comprehensive search in PubMed/Medline was conducted related to AMP general structure, function, signaling, expression, distribution and barrier function of AMP in the FRT, hormone regulation of AMP, the microbiome of the FRT, and AMP in relation to implantation, pregnancy, fertility, pelvic inflammatory disease, complications of pregnancy and assisted reproductive technology. RESULTS AMP are amphipathic peptides that target microbes for destruction and have been conserved throughout all living organisms. In the FRT, several major classes of AMP are expressed constitutively and others are inducible at the mucosal epithelium and by immune cells. AMP expression is also under the influence of sex hormones, varying throughout the menstrual cycle, and dependent on the vaginal microbiome. AMP can prevent infection with sexually transmissible and opportunistic pathogens of the female reproductive tissues, although emerging understanding of vaginal dysbiosis suggests induction of a unique AMP profile with increased susceptibility to these pathogens. During pregnancy, AMP are key immune effectors of the fetal membranes and placenta and are dysregulated in states of intrauterine infection and other complications of pregnancy. CONCLUSIONS At the level of the FRT, AMP serve to inhibit infection by sexually and vertically transmissible as well as by opportunistic bacteria, fungi, viruses, and protozoa and must do so throughout the hormone flux of menses and pregnancy. Guarding the exclusive site of reproduction, AMP modulate the vaginal microbiome of the lower FRT to aid in preventing ascending microbes into the upper FRT. Evolving in parallel with, and in response to, pathogenic insults, AMP are relatively immune to the resistance mechanisms employed by rapidly evolving pathogens and play a key role in barrier function and host defense throughout the FRT.
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Affiliation(s)
- Victoria L Yarbrough
- Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, , Phoenix, AZ 85004-2157, USA
| | - Sean Winkle
- Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, , Phoenix, AZ 85004-2157, USA
| | - Melissa M Herbst-Kralovetz
- Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, , Phoenix, AZ 85004-2157, USA
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15
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Van Hede D, Langers I, Delvenne P, Jacobs N. Origin and immunoescape of uterine cervical cancer. Presse Med 2014; 43:e413-21. [PMID: 25448124 DOI: 10.1016/j.lpm.2014.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/09/2014] [Indexed: 01/19/2023] Open
Abstract
Human papillomavirus associated uterine cervical cancer is an important public health problem since it is classified as the fourth most common cancer in women worldwide with more than 500,000 recorded cases. This review is focused on where and why HPV infection induces cervical cancers and how this virus avoids the host immune response. Immunological therapeutic approaches are also addressed.
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Affiliation(s)
- Dorien Van Hede
- University of Liège, cellular and molecular immunology, GIGA-Research, 4000 Liège, Belgium
| | - Inge Langers
- University of Liège, cellular and molecular immunology, GIGA-Research, 4000 Liège, Belgium
| | - Philippe Delvenne
- University of Liège, experimental pathology, GIGA-Research, 4000 Liège, Belgium
| | - Nathalie Jacobs
- University of Liège, cellular and molecular immunology, GIGA-Research, 4000 Liège, Belgium.
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16
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Torres-Poveda K, Bahena-Román M, Madrid-González C, Burguete-García AI, Bermúdez-Morales VH, Peralta-Zaragoza O, Madrid-Marina V. Role of IL-10 and TGF-β1 in local immunosuppression in HPV-associated cervical neoplasia. World J Clin Oncol 2014; 5:753-763. [PMID: 25302175 PMCID: PMC4129538 DOI: 10.5306/wjco.v5.i4.753] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 04/05/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus (HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin (IL)-10 and transforming growth factor (TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC I, NIC II and NIC III and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.
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17
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Hubert P, Herman L, Roncarati P, Maillard C, Renoux V, Demoulin S, Erpicum C, Foidart JM, Boniver J, Noël A, Delvenne P, Herfs M. Altered α-defensin 5 expression in cervical squamocolumnar junction: implication in the formation of a viral/tumour-permissive microenvironment. J Pathol 2014; 234:464-77. [PMID: 25196670 DOI: 10.1002/path.4435] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 08/10/2014] [Accepted: 09/02/2014] [Indexed: 11/07/2022]
Abstract
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix, which mainly develops at the squamocolumnar (SC) junction. The progression of cervical HPV infections into (pre)neoplastic lesions suggests that viral antigens are not adequately recognized by innate immunity or presented to the adaptive immune system. Members of the defensin family have recently been found to inhibit viral and bacterial pathogens, to stimulate the migration of immune cells and to play a role in anticancer responses. In the present study, we focused on the poorly characterized human α-defensin 5 (HD-5) and its possible role in these processes. We showed that HD-5 was able to prevent HPV virion entry into cervical keratinocytes and to influence adaptive immunity. Indeed, this peptide specifically induced the chemoattraction and proliferation of both activated T lymphocytes and immature dendritic cells in a CCR2/CCR6-dependent manner and stimulated the infiltration of these professional antigen-presenting cells in a (pre)neoplastic epithelium transplanted in vivo in immunodeficient mice. No chemotactic effect was observed with plasmacytoid dendritic cells, macrophages or natural killer cells. Proliferative and angiogenic effects of HD-5 were also assessed in vitro and in vivo. However there was a striking regional disparity in expression of HD-5, being prominent in ectocervical, vaginal and vulvar neoplasia, while absent, or nearly so, in the cervical SC junction. Taken together, these results suggest one possible explanation for why the SC junction is uniquely vulnerable to both high-risk HPV infection (via reduced HD-5 expression and viral entry) and progression of neoplasia (via altered cell-mediated immune responses and altered microenvironment).
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Affiliation(s)
- Pascale Hubert
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Belgium
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18
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Pahne-Zeppenfeld J, Schröer N, Walch-Rückheim B, Oldak M, Gorter A, Hegde S, Smola S. Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9-expressing dendritic cells. Int J Cancer 2014; 134:2061-73. [PMID: 24136650 DOI: 10.1002/ijc.28549] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 09/09/2013] [Accepted: 09/27/2013] [Indexed: 12/14/2022]
Abstract
Cervical carcinogenesis is a consequence of persistent infection with high-risk human papillomaviruses (HPVs). Recent studies indicate that HPV-transformed cells actively instruct their microenvironment to promote carcinogenesis. Here, we demonstrate that cervical cancer cells activate monocytes to produce their own CCL2 for further monocyte recruitment and reprogram their function during differentiation and maturation to dendritic cells (DCs). Our data show that cervical cancer cells suppress the induction of the chemokine receptor CCR7 in phenotypically mature DCs and impair their migration toward a lymph node homing chemokine, required to initiate adaptive immune responses. We confirmed the presence of CD83(+)CCR7(low) DCs in cancer biopsies. The second factor essential for DC migration, matrix-metalloproteinase MMP-9, which also has vasculogenic and protumorigenic properties, is not suppressed but upregulated in immature as well as mature DCs. We identified interleukin-6 (IL-6) as a crucial cervical cancer cell-derived mediator and nuclear factor kappaB (NF-jB) as the central signaling pathway targeted in DCs. Anti-IL-6 antibodies reverted not only NF-jB inhibition and restored CCR7-dependent migration but also blocked MMP-9 induction. This is the first report demonstrating the dissociation of CCR7 and MMP-9 expression in phenotypically mature CD83(+) DCs by cancer cells. Our results show that cervical cancer cells actively shape the local microenvironment. They induce the accumulation of myeloid cells and skew their function from immune activation to local production of protumorigenic MMP-9. Neutralizing anti-IL-6 antibodies can counteract this functional dysbalance and should therefore be considered for adjuvant cervical cancer therapy.
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19
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Prognostic significance of immunohistochemical phenotypes in patients treated for high-grade cervical intraepithelial neoplasia. BIOMED RESEARCH INTERNATIONAL 2013; 2013:831907. [PMID: 24455729 PMCID: PMC3878632 DOI: 10.1155/2013/831907] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Revised: 10/02/2013] [Accepted: 10/04/2013] [Indexed: 12/16/2022]
Abstract
Strong evidence exists that the host's immune system plays a crucial role for the development of human papillomavirus-related cervical premalignant and malignant lesions. In particular, effective cell-mediated immunity (CMI) promotes spontaneous infection clearance and cancer precursors regression in healthy subjects, while immunosuppressed individuals are more likely to experience infection persistence, cervical intraepithelial neoplasia (CIN) lesions, and cervical cancer. In this study, the prognostic significance of immunohistochemical profiling of CD4+ T-cells, CD8+ T-cells, dendritic cells (CD11c+), T-bet+, and GATA-3+ transcription factors has been studied in surgical specimens of 34 consecutive women affected by high-grade cervical intraepithelial neoplasia (CIN2-3) submitted to cervical conization. Results have been correlated with the clinical outcomes at 24 months after treatment and statistically analyzed. Higher rates of CD4+ T-cells, CD11c+ dendritic cells, and T-bet+ transcription factor positivity showed a strong statistically significative correlation with favourable clinical outcomes (P ≤ 0.0001). These data reinforce the evidence of the relevance of the host's immune status in the natural history of HPV-related cervical disease and add a prognostic significance of the cervical immunological profile in terms of predicting significant lower recurrence rates.
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20
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Pan YZ, Wang HL, Wang F, Luo D. Changes in distribution and ultrastructure of Langerhans cells in condyloma acuminatum tissues, and analysis of the underlying mechanism. DERMATOL SIN 2013. [DOI: 10.1016/j.dsi.2012.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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21
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Robertson SA, Prins JR, Sharkey DJ, Moldenhauer LM. Seminal fluid and the generation of regulatory T cells for embryo implantation. Am J Reprod Immunol 2013; 69:315-30. [PMID: 23480148 DOI: 10.1111/aji.12107] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Accepted: 01/30/2013] [Indexed: 12/13/2022] Open
Abstract
T regulatory (Treg) cells are essential mediators of the maternal immune adaptation necessary for embryo implantation. In mice, insufficient Treg cell activity results in implantation failure, or constrains placental function and fetal growth. In women, Treg cell deficiency is linked with unexplained infertility, miscarriage, and pre-eclampsia. To devise strategies to improve Treg cell function, it is essential to define the origin of the Treg cells in gestational tissues, and the regulators that control their functional competence and recruitment. Male seminal fluid is a potent source of the Treg cell-inducing agents TGFβ and prostaglandin E, and coitus is one key factor involved in expanding the pool of inducible Treg cells that react with paternal alloantigens shared by conceptus tissues. In mice, coitus initiates a sequence of events whereby female dendritic cells cross-present seminal fluid antigens and activate T cells, which in turn circulate via the blood to be sequestered into the endometrium. Similar events may occur in the human genital tract, where seminal fluid induces immune cell changes that appear competent to prime Treg cells. Improved understanding of how seminal fluid influences Treg cells in women should ultimately assist in the development of new therapies for immune-mediated pathologies of pregnancy.
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Affiliation(s)
- Sarah A Robertson
- Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia.
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22
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Deligeoroglou E, Giannouli A, Athanasopoulos N, Karountzos V, Vatopoulou A, Dimopoulos K, Creatsas G. HPV infection: immunological aspects and their utility in future therapy. Infect Dis Obstet Gynecol 2013; 2013:540850. [PMID: 24023507 PMCID: PMC3762170 DOI: 10.1155/2013/540850] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Accepted: 07/18/2013] [Indexed: 01/03/2023] Open
Abstract
High prevalence and mortality rates of cervical cancer create an imperative need to clarify the uniqueness of HPV (Human Papillomavirus) infection, which serves as the key causative factor in cervical malignancies. Understanding the immunological details and the microenvironment of the infection can be a useful tool for the development of novel therapeutic interventions. Chronic infection and progression to carcinogenesis are sustained by immortalization potential of HPV, evasion techniques, and alterations in the microenvironment of the lesion. Inside the lesion, Toll-like receptors expression becomes irregular; Langerhans cells fail to present the antigens efficiently, tumor-associated macrophages aggregate resulting in an unsuccessful immune response by the host. HPV products also downregulate the expression of microenvironment components which are necessary for natural-killer cells response and antigen presentation to cytotoxic cells. Additionally HPV promotes T-helper cell 2 (Th2) and T-regulatory cell phenotypes and reduces Th1 phenotype, leading to suppression of cellular immunity and lesion progression to cancer. Humoral response after natural infection is inefficient, and neutralizing antibodies are not adequate in many women. Utilizing this knowledge, new endeavors, such as therapeutic vaccination, aim to stimulate cellular immune response against the virus and alter the milieu of the lesion.
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Affiliation(s)
- Efthimios Deligeoroglou
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, Athens University, Medical School, Aretaieion Hospital, Vassilisis, Sofias Avenue 76, 11528 Athens, Greece
| | - Aikaterini Giannouli
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, Athens University, Medical School, Aretaieion Hospital, Vassilisis, Sofias Avenue 76, 11528 Athens, Greece
| | - Nikolaos Athanasopoulos
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, Athens University, Medical School, Aretaieion Hospital, Vassilisis, Sofias Avenue 76, 11528 Athens, Greece
| | - Vasileios Karountzos
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, Athens University, Medical School, Aretaieion Hospital, Vassilisis, Sofias Avenue 76, 11528 Athens, Greece
| | - Anastasia Vatopoulou
- Division of Pediatric and Adolescent Gynecology, 1st Department of Ob/Gyn Papageorgiou Hospital, University of Thessaloniki, Medical School, Perifereiaki Odos Thessalonikis-N, Efkarpias, 564 29 Thessaloniki, Greece
| | - Konstantinos Dimopoulos
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, Athens University, Medical School, Aretaieion Hospital, Vassilisis, Sofias Avenue 76, 11528 Athens, Greece
| | - George Creatsas
- Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, Athens University, Medical School, Aretaieion Hospital, Vassilisis, Sofias Avenue 76, 11528 Athens, Greece
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An interleukin-10 gene polymorphism associated with the development of cervical lesions in women infected with Human Papillomavirus and using oral contraceptives. INFECTION GENETICS AND EVOLUTION 2013; 19:32-7. [PMID: 23800422 DOI: 10.1016/j.meegid.2013.06.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 06/12/2013] [Accepted: 06/14/2013] [Indexed: 12/13/2022]
Abstract
Human Papillomavirus (HPV) infection plays a crucial role in the development of cervical lesions and tumors, however most lesions containing high-risk HPVs do not progress to cervical tumors. Some studies suggest that the use of oral contraceptives may increase the risk of cervical carcinogenesis, but this has not been confirmed by all the studies. Cytokines are important molecules that act in the defense of an organism against viral infections. Several genetic studies have attempted to correlate cytokine polymorphisms with human diseases, including cancer. The significance of IL10 polymorphisms for cancer is that they have both immunosuppressive and antiangiogenic properties. We aimed to investigate the role of promoter polymorphisms in the IL10 gene in women with cervical lesions associated with HPV infection, in the presence of the use of oral contraceptives. Using High Resolution Melt analysis (HRM), we analyzed an SNP -1082A/G and -819C/T in interleukin-10 promoter region in 364 Brazilian women: 171 with cervical lesions and HPV infection, and 193 with normal cytological results and HPV-negative. We observed no significant differences in genotype and allele frequencies in the two loci between patients and healthy controls. Furthermore, in the haplotype analysis of IL10, we found that CA haplotype was significantly more frequent in patients infected with HPV than in the control group (p = 0.0188). We did not find any genotype and allelic association of the IL10 gene polymorphisms between cases and controls. However, in this study, when the HPV-positive patients were stratified according to their use of contraceptives, we found a significant association between the -1082G allele (p = 0.0162) and -1082GG genotype (p = 0.0332) among HPV-infected patients who used oral contraceptives. Our findings suggest that -1082A/G gene polymorphism represents a greater susceptibility to progressive cervical lesions in HPV- infected women who use oral contraceptives.
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24
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Domingos-Pereira S, Decrausaz L, Derré L, Bobst M, Romero P, Schiller JT, Jichlinski P, Nardelli-Haefliger D. Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice. Mucosal Immunol 2013; 6:393-404. [PMID: 22968420 PMCID: PMC3573262 DOI: 10.1038/mi.2012.83] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased ~fivefold the number of vaccine-specific interferon-γ-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.
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Affiliation(s)
- Sonia Domingos-Pereira
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Loane Decrausaz
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Laurent Derré
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Martine Bobst
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Pedro Romero
- Ludwig Center for Cancer, Research of the University of Lausanne, CH-1011 Lausanne, Switzerland
| | - John T. Schiller
- Laboratory of Cellular Oncology, National Cancer Institute, NIH Bethesda, MD, USA
| | - Patrice Jichlinski
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Denise Nardelli-Haefliger
- Dpt. Urology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
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25
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Harbison CE, Ellis ME, Westmoreland SV. Spontaneous cervicovaginal lesions and immune cell infiltrates in nonhuman primates. Toxicol Pathol 2013; 41:1016-27. [PMID: 23427274 DOI: 10.1177/0192623313477754] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Nonhuman primates, particularly rhesus macaques (Macaca mulatta), provide important model systems for studying human reproductive infectious diseases such as human immunodeficiency virus, human papillomavirus, and Chlamydia spp. An understanding of the spectrum of spontaneous cervical disease provides essential context for interpreting experimental disease outcomes in the female reproductive tract. This retrospective study characterizes the incidence of inflammatory and/or proliferative cervicovaginal lesions seen over a 14-year period in a multispecies nonhuman primate colony, focusing on rhesus macaques. The most common observations included a spectrum of lymphocytic accumulation from within normal limits to lymphoplasmacytic cervicitis, and suppurative inflammation with occasional squamous metaplasia or polyp formation. These inflammatory spectra frequently occurred in the context of immunosuppression following experimental simian immunodeficiency virus (SIV) infection. Cervical neoplasias were uncommon and included leiomyomas and carcinomas. Cervical sections from 13 representative cases, with an emphasis on proliferative and dysplastic lesions, were surveyed for leukocyte infiltration, abnormal epithelial proliferation, and the presence of papillomavirus antigens. Proliferative lesions showed sporadic evidence of spontaneous papillomavirus infection and variable immune cell responses. These results underscore the importance of pre screening potential experimental animals for the presence of preexisting reproductive tract disease, and the consideration of normal variability within cycling reproductive tracts in interpretation of cervical lesions.
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Affiliation(s)
- Carole E Harbison
- 1New England Primate Research Center-Division of Comparative Pathology, Southborough, Massachusetts, USA
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26
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Sharkey DJ, Tremellen KP, Jasper MJ, Gemzell-Danielsson K, Robertson SA. Seminal fluid induces leukocyte recruitment and cytokine and chemokine mRNA expression in the human cervix after coitus. THE JOURNAL OF IMMUNOLOGY 2012; 188:2445-54. [PMID: 22271649 DOI: 10.4049/jimmunol.1102736] [Citation(s) in RCA: 260] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
In mice, seminal fluid elicits an inflammation-like response in the female genital tract that activates immune adaptations to advance the likelihood of conception and pregnancy. In this study, we examined whether similar changes in leukocyte and cytokine parameters occur in the human cervix in response to the male partner's seminal fluid. After a period of abstinence in proven-fertile women, duplicate sets of biopsies were taken from the ectocervix in the periovulatory period and again 48 h later, 12 h after unprotected vaginal coitus, vaginal coitus with use of a condom, or no coitus. A substantial influx of CD45(+) cells mainly comprising CD14(+) macrophages and CD1a(+) dendritic cells expressing CD11a and MHC class II was evident in both the stratified epithelium and deeper stromal tissue after coitus. CD3(+)CD8(+)CD45RO(+) T cells were also abundant and increased after coitus. Leukocyte recruitment did not occur without coitus or with condom-protected coitus. An accompanying increase in CSF2, IL6, IL8, and IL1A expression was detected by quantitative RT-PCR, and microarray analysis showed genes linked with inflammation, immune response, and related pathways are induced by seminal fluid in cervical tissues. We conclude that seminal fluid introduced at intercourse elicits expression of proinflammatory cytokines and chemokines, and a robust recruitment of macrophages, dendritic cells, and memory T cells. The leukocyte and cytokine environment induced in the cervix by seminal fluid appears competent to initiate adaptations in the female immune response that promote fertility. This response is also relevant to transmission of sexually transmitted pathogens and potentially, susceptibility to cervical metaplasia.
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Affiliation(s)
- David J Sharkey
- The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia 5005, Australia
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Bergot AS, Kassianos A, Frazer IH, Mittal D. New Approaches to Immunotherapy for HPV Associated Cancers. Cancers (Basel) 2011; 3:3461-95. [PMID: 24212964 PMCID: PMC3759206 DOI: 10.3390/cancers3033461] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 08/26/2011] [Accepted: 08/29/2011] [Indexed: 02/08/2023] Open
Abstract
Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, major oncogenic genotypes HPV-16 and -18). Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP) technology, have the potential to prevent a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumors expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. In humans, clinical trials have reported successful immunotherapy of HPV lesions, providing hope and further interest. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in our knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials.
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Affiliation(s)
- Anne-Sophie Bergot
- Author to whom correspondence should be addressed; E-Mails: (A.-S.B); (D.M.); Tel.: +61 (07) 3176 2769; Fax: +61 7 3176 5946
| | | | | | - Deepak Mittal
- Author to whom correspondence should be addressed; E-Mails: (A.-S.B); (D.M.); Tel.: +61 (07) 3176 2769; Fax: +61 7 3176 5946
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Bhat P, Mattarollo SR, Gosmann C, Frazer IH, Leggatt GR. Regulation of immune responses to HPV infection and during HPV-directed immunotherapy. Immunol Rev 2011; 239:85-98. [PMID: 21198666 DOI: 10.1111/j.1600-065x.2010.00966.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The recent development of vaccines prophylactic against human papillomavirus (HPV) infection has the potential to reduce the incidence of cervical cancer globally by up to 70% over the next 40 years, if universal immunization is adopted. As these prophylactic vaccines do not alter the natural history of established HPV infection, immunotherapies to treat persistent HPV infection and associated precancers would be of benefit to assist with cervical cancer control. Efforts to develop immuno-therapeutic vaccines have been hampered by the relative non-immunogenicity of HPV infection, by immunoregulatory processes in skin, and by subversion of immune response induction and immune effector functions by papillomavirus proteins. This review describes HPV-specific immune responses induced by viral proteins, their regulation by host and viral factors, and highlights some conclusions from our own recent research.
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Affiliation(s)
- Purnima Bhat
- The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia
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Pereira KMA, Soares RC, Oliveira MC, Pinto LP, Costa ADLL. Immunohistochemical staining of Langerhans cells in HPV-positive and HPV-negative cases of oral squamous cells carcinoma. J Appl Oral Sci 2011; 19:378-83. [PMID: 21710097 PMCID: PMC4223790 DOI: 10.1590/s1678-77572011005000013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2009] [Accepted: 10/26/2010] [Indexed: 11/21/2022] Open
Abstract
The Human Papillomavirus (HPV) has been strongly implicated in development of
some cases of oral squamous cell carcinoma (OSCC). However, the immunological
system somehow reacts against the presence of this virus. Among the cells
involved in such mechanism of defense Langerhans cells (LC) stand out, which are
responsible for processing and presenting antigens.
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Mucosal junctions: open doors to HPV and HIV infections? Trends Microbiol 2011; 19:114-20. [DOI: 10.1016/j.tim.2010.12.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Revised: 12/09/2010] [Accepted: 12/14/2010] [Indexed: 12/29/2022]
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Rodríguez AC, García-Piñeres AJ, Hildesheim A, Herrero R, Trivett M, Williams M, Atmella I, Ramírez M, Villegas M, Schiffman M, Burk R, Freer E, Bonilla J, Bratti C, Pinto LA. Alterations of T-cell surface markers in older women with persistent human papillomavirus infection. Int J Cancer 2011; 128:597-607. [PMID: 20473864 DOI: 10.1002/ijc.25371] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We previously reported decreased lymphocyte proliferative responses among older women with persistent human papillomavirus (HPV) infection. To characterize the phenotype of peripheral lymphocytes associated with persistent HPV infection, we evaluated the expression of different cell surface markers in peripheral blood mononuclear cells (PBMCs) from a case-control study within a 10,049 woman population-based cohort study in Guanacaste, Costa Rica. Women in the cohort aged 46-74 and with HPV results at their 5th year anniversary visit were considered, and all women (n = 87) with persistent HPV infections, all women (n = 196) with transient HPV infections and a random sample of HPV DNA-negative women (n = 261) frequency-matched to cases on age were selected for this study. A median of 3 years after the case-control matching visit, cervical cells were collected for liquid-based cytology and repeat HPV DNA genotyping. Blood was obtained from which PBMCs were extracted and cryopreserved for immunological phenotyping via flow cytometry. Significant increases in risk of HPV persistence were observed for 3 marker subsets indicative of immune cell activation/differentiation. Relative risk estimates were 5.4 (95% CI = 2.2-13.3) for CD69(+)CD4(+), 2.6 (95% CI = 1.2-5.9) for HLADR(+)CD3(+)CD4(+) and 2.3 (95% CI = 1.1-4.7) for CD45RO(+)CD27(-)CD8(+). A significant decrease in HPV persistence was observed for a subset marker indicative of an immature, undifferentiated memory state CD45RO(+)CD27(+)CD4(+) (OR = 0.36; 95% CI = 0.17-0.76). Adjustment for these markers only partially explained the previously reported association between decreased lymphoproliferative responses and persistent HPV infection. Whether phenotypic alterations observed predispose to HPV persistence or result from it should be the focus of future studies.
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Affiliation(s)
- Ana Cecilia Rodríguez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Herman L, Hubert P, Herfs M, Kustermans G, Henrotin Y, Bousarghin L, Boniver J, Delvenne P. The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context. Eur J Immunol 2010; 40:3075-84. [DOI: 10.1002/eji.201040571] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Oliveira PM, Oliveira RPC, Travessa IÉM, Gomes MVDC, dos Santos MLDJ, Grassi MFR. Prevalence and risk factors for cervical intraepithelial neoplasia in HIV-infected women in Salvador, Bahia, Brazil. SAO PAULO MED J 2010; 128:197-201. [PMID: 21120429 PMCID: PMC10938988 DOI: 10.1590/s1516-31802010000400004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2009] [Revised: 06/11/2010] [Accepted: 06/11/2010] [Indexed: 11/22/2022] Open
Abstract
CONTEXT AND OBJECTIVE The human immunodeficiency virus (HIV) is frequently associated with high-grade intraepithelial neoplasia. Immunosuppression and high HIV viral load are the main risk factors for cervical intraepithelial neoplasia (CIN). The aim of this study was to determine the prevalence of CIN in HIV-infected women in Salvador, Bahia, Brazil, and to describe the risk factors in comparison with non-infected women. DESIGN AND SETTING Cross-sectional study at the AIDS Reference Center of Bahia and the Gynecological Outpatient Clinic of Fundação Bahiana para o Desenvolvimento da Ciência, in Salvador, Bahia, Brazil. METHODS Sixty-four HIV-infected women and 76 uninfected women from Salvador were enrolled between May 2006 and May 2007. Associations between CIN and presence of HIV infection, HIV viral load, proportion of T CD4+ lymphocytes and risk factors were evaluated. The independence of the risk factors was investigated using logistic regression. RESULTS CIN was more prevalent among HIV-infected women than in the control group (26.6% versus 6.6%; P = 0.01). The odds ratio for CIN among HIV-infected women was 3.7 (95% confidence interval, CI: 1.23-11; P = 0.01), after adjusting for the following variables: age at first sexual intercourse, number of partners, number of deliveries and previous history of sexually transmitted disease. CONCLUSION The prevalence of CIN among HIV-infected women was significantly higher than among women without HIV infection. HIV infection was the most important risk factor associated with the development of cervical lesions.
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Affiliation(s)
- Paula Matos Oliveira
- MD. Doctoral student in the Postgraduate Program on Medicine and Human Health, Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, Bahia, Brazil.
| | - Rone Peterson Cerqueira Oliveira
- MD, MSc. Assistant professor, Gynecological Service, Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, Bahia, Brazil.
| | | | | | - Maria Lícia de Jesus dos Santos
- MD. Gynecologist at the AIDS Reference Center of Bahia (Centro Especializado em Diagnóstico, Assistência e Pesquisa, CEDAP), Salvador, Bahia, Brazil.
| | - Maria Fernanda Rios Grassi
- MD, PhD. Head of the Advanced Public Health Laboratory, Centro de Pesquisa Gonçalo Muniz (CPqGM), Fundação Oswaldo Cruz (Fiocruz), Salvador, Bahia, Brazil.
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Hubert P, Doyen J, Capelle X, Arafa M, Renoux V, Bisig B, Seidel L, Evrard B, Bousarghin L, Gerday C, Boniver J, Foidart JM, Delvenne P, Jacobs N. Local applications of GM-CSF induce the recruitment of immune cells in cervical low-grade squamous intraepithelial lesions. Am J Reprod Immunol 2010; 64:126-36. [PMID: 20367631 DOI: 10.1111/j.1600-0897.2010.00834.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
PROBLEM Quantitative alterations of antigen-presenting cells (APC) in (pre)neoplastic lesions of the uterine cervix associated with human papillomavirus (HPV) infection suggest a diminished capacity to capture viral antigens and to induce a protective immune response. METHOD OF STUDY To test whether a cervical application of GM-CSF could restore an immune response against HPV in women with cervical low-grade squamous intraepithelial lesions (LSIL), we performed two clinical trials with 11 healthy women and 15 patients with LSIL. RESULTS GM-CSF applications were well tolerated in all enrolled women, and no difference in toxicity between the treated and placebo groups was observed during the follow-up (until 30 months). Interestingly, in the GM-CSF treated group, a significant increase of APC and cytotoxic T-lymphocyte infiltration was observed in the cervical biopsies with no change in regulatory T cell numbers. All the HPV16(+) patients exhibited an immune response against HPV16 after GM-CSF applications, as shown by NK and/or T cells producing IFN-gamma whereas no cellular immune response was observed before the treatment. Moreover, the anti-virus-like particles antibody titers also increased after the treatment. CONCLUSION These encouraging results obtained from a limited number of subjects justify further study on the therapeutic effect of APC in cervical (pre)neoplastic lesions.
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Affiliation(s)
- Pascale Hubert
- Department of Pathology, GIGA-CANCER/GIGA-I3, University of Liège, B23 CHU Sart-Tilman, Liège, Belgium
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Laurson J, Khan S, Chung R, Cross K, Raj K. Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. Carcinogenesis 2010; 31:918-26. [PMID: 20123756 PMCID: PMC2864410 DOI: 10.1093/carcin/bgq027] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A common feature shared between several human cancer-associated viruses, such as Epstein-Barr virus, Hepatitis B virus and Hepatitis C virus, and Human papillomavirus (HPV) is the ability to reduce the expression of cellular E-cadherin. Since E-cadherin is used by Langerhans cells to move through the stratified epithelium, its reduction may affect the efficiency by which the immune system responds to HPV infection and the length of persistent HPV infections. We observed that the E7 protein of this virus (HPV16) is most efficient at reducing E-cadherin levels. This E7 activity is independent of retinoblastoma protein or AP-2α degradation. Instead it is associated with augmentation of cellular DNA methyltransferase I (Dnmt1) activity. Significantly, inhibition of Dnmt activity re-established E-cadherin levels of the cells, presenting the possibility that similar epigenetic intervention clinically may be a way to re-establish the influx of Langerhans cells into infected epithelium to counteract HPV persistence.
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Affiliation(s)
- Joanna Laurson
- Department of Virology, The National Institute for Medical Research, The Ridgeway Mill Hill, London NW7 1AA, UK
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Mougin C, Bourgault-Villada I, Coursaget P. [HPV immunization for the prevention of cervical cancer]. Presse Med 2009; 38:1750-68. [PMID: 19765945 DOI: 10.1016/j.lpm.2009.06.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 06/10/2009] [Accepted: 06/15/2009] [Indexed: 10/20/2022] Open
Abstract
CONTEXT Human Papillomaviruses (HPV) infect epithelial cells of the skin and mucosae. Mucosal high-risk HPV types (mainly HPV 16 and 18) are involved in the development of cervical cancer, one of the most common cancers in young women. HPV infection is usually asymptomatic and clears spontaneously, but 10 - 15 % of high-risk HPV infections are persistent and increase the risk of precancerous and cancerous lesions of the cervix. Two HPV vaccines have been licensed to provide protection against cervical cancer. OBJECTIVES To report the different aspects of HPV infection in order to improve the understanding of the particular problems of HPV vaccination and to review the most recent findings related to HPV vaccines, particularly regarding the protective efficacy of vaccines and the roles of adjuvants and immune response in protection. METHODS Articles were selected from the PubMed database (National Library of Medicine- National Institute of Health) with the following Keywords "HPV", "Prevention", "HPV vaccines", "Immune response", "Antibody". Abstracts of oral presentations from international meetings were also selected for the more recent findings. a critical analysis of the majority of papers published was undertaken and relevant information summarized. RESULTS Virus-like particle production by expressing the major protein of the HPV capsid was carried out in the early 90's, leading to the recent development of two HPV vaccines. These vaccines are now licensed in many countries and have been demonstrated to be highly immunogenic. In subjects that are non-infected at the time of vaccination, HPV vaccines are highly effective in preventing persistent HPV 16 - 18 infections (90 %) and precursors lesions of cervical cancer associated with these two HPV types (close to 100 %). Clinical trials have also confirmed that HPV vaccines are well tolerated by recipients. CONCLUSIONS The present paper is a detailed review published in French on HPV vaccines, their efficacy in the prevention of HPV infections and unresolved questions regarding the use of HPV vaccines. This report also includes biological and immunological information to improve the understanding of HPV vaccination.
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Affiliation(s)
- Christiane Mougin
- UFR des Sciences Médicales et Pharmaceutiques, EA 3181, IFR 133, Université de Franche-Comté, F-25000 Besançon, France
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Gonçalves MAG, Soares EG, Donadi EA. The influence of human papillomavirus type and HIV status on the lymphomononuclear cell profile in patients with cervical intraepithelial lesions of different severity. Infect Agent Cancer 2009; 4:11. [PMID: 19689792 PMCID: PMC2736163 DOI: 10.1186/1750-9378-4-11] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Accepted: 08/18/2009] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immunological alterations are implicated in the increased prevalence of high-grade squamous intraepithelial lesions (HG-SIL) and persistent human papillomavirus (HPV) infection. This study evaluated the expression of CD4, CD8, CD25 (IL-2Ralpha) and CD28 antigens from SIL biopsies, stratified by HIV status and HPV-type. Biopsies specimens from 82 (35 HIV+) women with a normal cervix, low-grade (LG-SIL) or high-grade lesions (HG-SIL) were studied. CD molecule expression was evaluated by immunohistochemistry and HPV detection/typing performed using PCR techniques. RESULTS CD4 stromal staining was increased in patients with HPV18. Women with HPV16 infection showed decreased: a) CD8 and CD25 stromal staining, b) CD25 staining in LG-SIL epithelium and in HG-SIL stroma. In HIV- women samples, CD28 epithelial staining and CD8 stromal staining surrounding metaplastic epithelium were less intense and even absent, as compared to HIV+ women. Both epithelial and stromal CD8 staining was more intense in the HG-SIL/HIV+ group than in the HG-SIL/HIV- group. Positive correlations were observed between CD4/CD25, CD4/CD28 and CD25/CD28 in the stroma and CD25/CD28 in the epithelium. CONCLUSION HIV status and HPV-type may influence the lymphomononuclear cell profile present in the spectrum of cervical lesions. The knowledge of the infiltrating cell profile in cervical tumours may help the development of specific anti-tumoural strategies.
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Affiliation(s)
- Maria Alice G Gonçalves
- Division of Clinical Immunology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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Abstract
PURPOSE OF REVIEW The purpose of this review is to understand the role of the host immune system in clearing the human papillomavirus (HPV) infection, strategies adopted by HPV to subvert the host immune responses and analyze the challenges to the future immunotherapeutic treatment modalities. RECENT FINDINGS Cervical epithelium provides a protective niche to the virus to subvert the immune responses. The absence of an inflammatory milieu in the cervix makes the resident dendritic and langerhan cells tolerogenic to HPV antigens. CD4 cells predominated in regressing cervical intraepithelial neoplasia lesions, whereas CD8 cells were dominant in invasive carcinoma. A reduced expression of T cell signaling molecule T-cell receptor zeta chain was observed in CD8 lymphocytes. Decreased numbers of NKG2D expressing natural killer and T cells were present in patients with cervical cancer and cervical intraepithelial neoplasia. Increased frequencies of CD4 CD25+ FoxP3+ T regulatory cells were observed in patients with cervical cancer. The Nrp-1+Treg showed greater suppressive activity. A network of Treg and indoleamine 2, 3-dioxygenase expressed in tumor cells facilitates immune escape of tumor cells. SUMMARY The HPV uses different strategies to evade immune recognition. Understanding the immune evasion mechanisms used by HPV will help in designing newer therapeutic strategies for cervical cancer.
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Affiliation(s)
- Swati Patel
- Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
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Einstein MH, Schiller JT, Viscidi RP, Strickler HD, Coursaget P, Tan T, Halsey N, Jenkins D. Clinician's guide to human papillomavirus immunology: knowns and unknowns. THE LANCET. INFECTIOUS DISEASES 2009; 9:347-56. [DOI: 10.1016/s1473-3099(09)70108-2] [Citation(s) in RCA: 154] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Herfs M, Hubert P, Delvenne P. Epithelial metaplasia: adult stem cell reprogramming and (pre)neoplastic transformation mediated by inflammation? Trends Mol Med 2009; 15:245-53. [PMID: 19457719 DOI: 10.1016/j.molmed.2009.04.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Revised: 04/03/2009] [Accepted: 04/03/2009] [Indexed: 12/17/2022]
Abstract
Throughout adult life, new developmental commitment of adult stem cells causes metaplastic conversions to occur frequently in some organs. These reversible epithelial replacements are almost always observed in association with chronic inflammation and persistent irritation. Although metaplasia is not synonymous with dysplasia, clinical surveillance has demonstrated that these adaptive processes have an increased susceptibility to evolve into cancer. We propose that cytokines and other soluble factors released by both epithelial and inflammatory cells might alter the transcription-factor expression profile of stem cells and lead to the development of metaplasia. Furthermore, inflammatory mediators might also promote the malignant transformation of epithelial metaplasia by inducing genetic and epigenetic changes and by preventing the immune system from mounting an efficient anti-tumour immune response. A better understanding of the molecular mechanisms leading to metaplasia might help in the design of new therapies for neoplastic and degenerative diseases.
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Affiliation(s)
- Michael Herfs
- Laboratory of Experimental Pathology, GIGA-Cancer (Centre for Experimental Cancer Research), University of Liege, Liege, Belgium
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Herfs M, Herman L, Hubert P, Minner F, Arafa M, Roncarati P, Henrotin Y, Boniver J, Delvenne P. High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells. Cancer Immunol Immunother 2009; 58:603-14. [PMID: 18802697 PMCID: PMC11030941 DOI: 10.1007/s00262-008-0584-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2007] [Accepted: 08/23/2008] [Indexed: 11/28/2022]
Abstract
Although human papillomavirus (HPV) DNA is detected in the majority of squamous intraepithelial lesions (SIL) and carcinoma (SCC) of the uterine cervix, the persistence or progression of cervical lesions suggest that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most SIL show quantitative and functional alterations of Langerhans cells (LC). The aim of this study was to determine whether prostaglandins (PG) may affect LC density in the cervical (pre)neoplastic epithelium. We first demonstrated that the epithelial expression of PGE(2) enzymatic pathways, including cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), is higher in SIL and SCC compared to the normal exocervical epithelium and inversely correlated to the density of CD1a-positive LC. By using cell migration assays, we next showed that the motility of immature dendritic cells (DC) and DC partially differentiated in vitro in the presence of PGE(2) are differentially affected by PGE(2). Immature DC had a lower ability to migrate in the presence of PGE(2) compared to DC generated in vitro in the presence of PGE(2). Finally, we showed that PGE(2) induced a cytokine production profile and phenotypical features of tolerogenic DC, suggesting that the altered expression of PGE(2) enzymatic pathways may promote the cervical carcinogenesis by favouring (pre)cancer immunotolerance.
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Affiliation(s)
- Michaël Herfs
- Department of Pathology B23, GIGA Cancer, University of Liege, CHU Sart Tilman, 4000, Liège, Belgium.
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Louie KS, de Sanjose S, Diaz M, Castellsagué X, Herrero R, Meijer CJ, Shah K, Franceschi S, Muñoz N, Bosch FX. Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries. Br J Cancer 2009; 100:1191-7. [PMID: 19277042 PMCID: PMC2670004 DOI: 10.1038/sj.bjc.6604974] [Citation(s) in RCA: 131] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Early age at first sexual intercourse (AFSI) has long been associated with an increased risk of invasive cervical carcinoma (ICC). Age at first pregnancy (AFP) and ICC have been investigated less, although AFSI and AFP are strongly interrelated in most developing countries. A pooled analysis of case–control studies on ICC from eight developing countries with 1864 cases and 1719 controls investigated the roles of AFSI, AFP, and ICC risk. Age at first sexual intercourse, AFP and age at first marriage (AFM) were highly interrelated and had similar ICC risk estimates. Compared with women with AFSI ⩾21 years, the odds ratio (OR) of ICC was 1.80 (95% CI: 1.50–2.39) among women with AFSI 17–20 years and 2.31 (95% CI: 1.85–2.87) for AFSI ⩽16 years (P-trend <0.001). No statistical interaction was detected between AFSI and any established risk factors for ICC. The ICC risk was 2.4-fold among those who reported AFSI and AFP at ⩽16 years compared with those with AFSI and AFP at ⩾21 years. These data confirm AFSI and AFB as risk factors for ICC in eight developing countries, but any independent effects of these two events could not be distinguished.
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Affiliation(s)
- K S Louie
- Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Hospitalet del Llobregat (Barcelona), Barcelona, Spain.
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Kovalenko S, Lukashenko P, Romanovskaya A, Soldatski IL, Bakanov SI, Pfister H, Gerein V. Distribution and density of CD1a+ and CD83+ dendritic cells in HPV-associated laryngeal papillomas. Int J Pediatr Otorhinolaryngol 2009; 73:249-56. [PMID: 19062106 DOI: 10.1016/j.ijporl.2008.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Accepted: 10/21/2008] [Indexed: 01/16/2023]
Abstract
BACKGROUND Respiratory papillomatosis associated with human papilloma virus (HPV) infection is the most common benign laryngeal neoplasm. The age of patients at disease onset, HPV type, number of surgeries are well known prognostic factors of the disease course. The correlation between dendritic cell (DC) density in tumor tissue and clinical prognosis was established. AIM The aim of our study was to estimate the density of DC in laryngeal papillomas associated with HPV types 6/11 infection and to evaluate the relationship between the number of DC and the disease severity. MATERIALS AND METHODS Our study included 40 randomly selected biopsy specimens from patients with HPV-positive laryngeal papillomatosis aged from 1.7 to 20 year. DC were immunohistochemically labelled with anti-CD1a antibodies and anti-CD83 antibodies. The density of DC was analysed in epithelial layer and lamina propria. RESULTS In the epithelial layer of papillomas the number of CD1a+ and CD83+ DC was 86.2 (47.5-119.9) cells/mm(2) and 2.6 (0.6-7.9) cells/mm(2), respectively. In lamina propria - 15.3 (5.1-27.9) and 16.0 (6.7-33.2) cells/mm(2). For subgroups of patients with high number of operations (more than 3), early disease onset (children under 3 years of age) and lingering duration of disease (more than 1 year) we detected an increase of CD83+ DC in the epithelial layer. However, our data did not demonstrate a statistically significant difference in CD1a+ DC count neither in the epithelium nor in the lamina propria. Probably, the increase of CD83+ DC density in epithelial layer of patients with severe course of disease can be an evidence of impaired migration of matured DC.
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Affiliation(s)
- Sergey Kovalenko
- Department of Pediatric Pathology, Institute of Pathology, Johannes Gutenberg University of Mainz, Mainz, Germany.
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Bermudez-Morales VH, Gutierrez LX, Alcocer-Gonzalez JM, Burguete A, Madrid-Marina V. Correlation between IL-10 gene expression and HPV infection in cervical cancer: a mechanism for immune response escape. Cancer Invest 2009; 26:1037-43. [PMID: 18798072 DOI: 10.1080/07357900802112693] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The present study was performed to determine IL-10 expression in cervical tissues in Mexican women according to the severity of the malignity and its association with HPV infection. IL-10 expression showed a clear tendency to increase during the different cervical cancer stages: 37% in LGSIL; 62% in HGSIL; and 84% in cancer. However, all the patients that expressed IL-10 were HPV positives; we found an association with HPV 16. These results suggest a clear relationship between IL-10, HPV and the stage of cervical cancer disease; this event could contribute to the immunosuppressive micro-environment in the tumor site.
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Caberg JH, Hubert P, Herman L, Herfs M, Roncarati P, Boniver J, Delvenne P. Increased migration of Langerhans cells in response to HPV16 E6 and E7 oncogene silencing: role of CCL20. Cancer Immunol Immunother 2009; 58:39-47. [PMID: 18438663 PMCID: PMC11030152 DOI: 10.1007/s00262-008-0522-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2008] [Accepted: 04/11/2008] [Indexed: 12/29/2022]
Abstract
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The persistence or progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most squamous intraepithelial lesions (SILs) show quantitative and functional alterations of Langerhans cells (LC). The infiltration of immature LC in the squamous epithelium is mainly controlled by Macrophage Inflammatory Protein 3alpha/CCL20. After having shown that CCL20 production is altered in HPV-transformed keratinocytes (KC), the possible role of HPV16 E6 and E7 viral oncoproteins in the reduced CCL20 levels observed in SILs was investigated by silencing HPV16 E6 and E7 oncogenes by RNA interference (siRNA). This treatment not only increased CCL20 secretion but also resulted in the modulation of NF-kappaB p50, p52 and p65 precursor localization. Moreover, silencing of E6 and E7 oncogenes in HPV16-transformed KC induced a significantly higher migratory capacity of LC in a Boyden chamber assay and in an in vitro formed (pre)neoplastic epithelium reminiscent of high-grade SILs. Anti-CCL20 neutralizing antibody experiments showed that the increased migration of LC is due to the re-expression of CCL20 in E6 and E7 siRNA transfected KC. These data suggest that HPV16 E6/E7-induced down-regulation of CCL20 observed during the cervical carcinogenesis may contribute to a diminished capacity of the immune system to control HPV infection.
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Affiliation(s)
- Jean-Hubert Caberg
- Department of Pathology, GIGA-Cancer, B35, University of Liege, CHU Sart Tilman, Liege, Belgium.
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Santegoets LAM, van Seters M, Heijmans-Antonissen C, Kleinjan A, van Beurden M, Ewing PC, Kühne LCM, Beckmann I, Burger CW, Helmerhorst TJM, Blok LJ. Reduced local immunity in HPV-related VIN: expression of chemokines and involvement of immunocompetent cells. Int J Cancer 2008; 123:616-22. [PMID: 18498128 DOI: 10.1002/ijc.23545] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of VIN in immuno-suppressed women suggests that a good innate and adaptive immune response is important for defense against HPV. Here, we explored expression levels of chemokines and related these to the presence or absence of immuno-competent cells (dendritic and T-cells) in affected (HPV-positive VIN) and non-affected (HPV-negative) vulvar tissues from the same patients. Combining microarray data with quantitative real-time RT-PCR, it was observed that several important chemokines were differentially expressed between VIN and control samples (up-regulation of IL8, CXCL10, CCL20 and CCL22 and down-regulation of CXCL12, CCL21 and CCL14). Furthermore, an increased number of mature dendritic cells (CD208+) seemed to be bottled up in the dermis, and although a T-cell response (increased CD4+ and CD8+ cells) was observed in VIN, a much larger response is required to clear the infection. In summary, it seems that most mature dendritic cells do not receive the proper chemokine signal for migration and will stay in the dermis, not able to present viral antigen to naive T-cells in the lymph node. Consequently the adaptive immune response diminishes, resulting in a persistent HPV infection with increased risk for neoplasia.
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Affiliation(s)
- Lindy A M Santegoets
- Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Caberg JHD, Hubert PM, Begon DY, Herfs MF, Roncarati PJ, Boniver JJ, Delvenne PO. Silencing of E7 oncogene restores functional E-cadherin expression in human papillomavirus 16-transformed keratinocytes. Carcinogenesis 2008; 29:1441-7. [PMID: 18566017 DOI: 10.1093/carcin/bgn145] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The persistence or progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most squamous intra-epithelial lesions show quantitative and functional alterations of Langerhans cells (LCs). Moreover, E-cadherin-dependent adhesion of LC to keratinocytes (KCs) is defective in cervical HPV16-associated (pre)neoplastic lesions. The possible role of viral oncoprotein E7 in the reduced levels of cell surface E-cadherin was investigated by silencing HPV16 E7 by RNA interference (siRNA). This treatment induced an increased cell surface E-cadherin expression in HPV16-positive KC and a significant adhesion of LC to these squamous cells. The E-cadherin re-expression following HPV16 E7 silencing was associated with increased detection levels of retinoblastoma protein and the activating protein (AP)-2alpha transcription factor. These data suggest that HPV16 E7-induced alterations of LC/KC adhesion may play a role in the defective immune response during cervical carcinogenesis.
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Affiliation(s)
- Jean-Hubert D Caberg
- Department of Pathology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, B23, University of Liege, Centre Hospitalier Universitaire Sart Tilman, 4000 Liege, Belgium.
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Herfs M, Hubert P, Kholod N, Caberg JH, Gilles C, Berx G, Savagner P, Boniver J, Delvenne P. Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:1391-402. [PMID: 18385519 DOI: 10.2353/ajpath.2008.071004] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a(+) LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-beta1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-beta1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis.
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Affiliation(s)
- Michael Herfs
- Department of Pathology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Cancer), University of Liege, 4000 Liege, Belgium.
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Intravaginal immunization of mice with recombinant Salmonella enterica serovar Typhimurium expressing human papillomavirus type 16 antigens as a potential route of vaccination against cervical cancer. Infect Immun 2008; 76:1940-51. [PMID: 18332214 DOI: 10.1128/iai.01484-07] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cervical cancer, the second leading cause of cancer deaths in women, is the consequence of high-risk human papillomavirus (HPV) infections. Toward the development of therapeutic vaccines that can induce both innate and adaptive mucosal immune responses, we analyzed intravaginal (ivag) vaccine delivery of live attenuated Salmonella enterica serovar Typhimurium expressing HPV16L1 as a model antigen. Innate immune responses were examined in cervicovaginal tissues by determining gene expression patterns by microarray analysis using nylon membranes imprinted with cDNA fragments coding for inflammation-associated genes. At 24 h, a wide range of genes, including those for chemokines and Th1- and Th2-type cytokine and chemokine receptors were up-regulated in mice ivag immunized with Salmonella compared to control mice. However, the majority of transcripts returned to their steady-state levels 1 week after immunization, suggesting a transient inflammatory response. Indeed, cervicovaginal histology of immunized mice showed a massive, but transient, infiltration of macrophages and neutrophils, while T cells were still increased after 7 days. Ivag immunization also induced humoral and antitumor immune responses, i.e., serum and vaginal anti-HPV16VLP antibody titers similar to those induced by oral immunization, and significant protection in tumor protection experiments using HPV16-expressing C3 tumor cells. These results show that ivag immunization with live attenuated Salmonella expressing HPV16 antigens modulates the local mucosal gene expression pattern into a transient proinflammatory profile, elicits strong systemic and mucosal immunity against HPV16, and confers protection against HPV16 tumor cells subcutaneously implanted in mice. Examination of the efficacy with which ivag HPV16E7E6 Salmonella induces regression of tumors located in cervicovaginal tissue is warranted.
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Feng JY, Peng ZH, Tang XP, Geng SM, Liu YP. Immunohistochemical and ultrastructural features of Langerhans cells in condyloma acuminatum. J Cutan Pathol 2008; 35:15-20. [PMID: 18095989 DOI: 10.1111/j.1600-0560.2007.00763.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND There are few studies on the abnormal morphology of Langerhans cells (LCs) in condyloma acuminatum (CA) lesions and the essence of the abnormal morphology of LCs in CA lesions is still not well elucidated. The aim of this study was to further investigate the morphological features of LCs in CA lesions. METHODS CD1a(+) LCs in 13 CA lesions and in 13 normal controls were labeled using immunohistochemistry and examined by light microscopy. Ultrastructural investigation on LCs in six CA lesions and in six normal controls was performed by electron microscopy. RESULTS Compared with those in normal controls, most CD1a(+) LCs in CA lesions exhibited dysplastic dendrities and abnormal distribution. The number of CD1a(+) LCs in CA lesions (26.31 +/- 18.84) was statistically lower (p < 0.001) than that in normal controls (72.00 +/- 27.40). Electron microscopy showed that the number of Birbeck granules within lesional LCs (4.00 +/- 2.94) was significantly decreased (p < 0.001) than that within normal LCs (10.80 +/- 4.78). The ultrastructures of most lesional LCs displayed degenerative changes. CONCLUSIONS The morphology of most LCs in CA lesions shows degenerative changes, which suggest that these LCs have been functionally impaired.
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Affiliation(s)
- Jin-Yun Feng
- Department of Dermatology, The Second Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
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