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Damani M, Mhaske A, Dighe S, Sawarkar SP. Immunotherapy in Cervical Cancer: An Evolutionary Paradigm in Women's Reproductive Health. Crit Rev Ther Drug Carrier Syst 2025; 42:55-88. [PMID: 40084517 DOI: 10.1615/critrevtherdrugcarriersyst.2025044498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Cervical cancer is the fourth most common cause of morbidity and mortality in women. The major causative factor for cervical cancer is primary prolonged infection with human papillomavirus, along with secondary factors such as immunodeficiency, smoking, low socioeconomic standards, poor hygiene, and overuse of oral contraceptives. A grave need exists to practice novel strategies to overcome existing drawbacks of conventional therapy such as chemotherapy, radiation therapy, and surgery. Cancer immunotherapy works by strengthening the immune system of the host to combat against the cancerous cells. Immunotherapy in cervical cancer treatment has demonstrated long-lasting effects; however, the response to such therapies was nominal due to its prominent limitations such as immunosuppressive behavior of the tumor. Presently plethora of nanoplatforms such as polymeric nanoparticles, micelles, liposomes, and dendrimers are being maneuvered with cancer immunotherapy. The amalgamation of nanotechnology and immunotherapy in the treatment of cervical cancer is conceivable due to the mutual association between the tumor microenvironment and immunosurveillance. Safety concerns of nanoplatforms with immunotherapeutics such as toxicity, inflammation, and unwanted accumulation in tissues could be surmounted by surface modification methods. This review highlights the benefits of the amalgamation of nanotechnology and immunotherapy to improve shortcomings applicable to the conventional delivery of cancer treatment. We also aim to outline the nanoimmunotherapy sophistications and future translational avenues in this rapidly flourishing cancer treatment modality.
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Affiliation(s)
- Mansi Damani
- Department of Pharmaceutics, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, University of Mumbai, Maharashtra, India
| | - Akshada Mhaske
- Department of Pharmaceutics, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, University of Mumbai, Mumbai, India
| | - Sayali Dighe
- Department of Pharmaceutics, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, University of Mumbai, Mumbai, India
| | - Sujata P Sawarkar
- Department of Pharmaceutics, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, University of Mumbai, V.L. Mehta Road, Vile Parle (West), Mumbai 400 056, India
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2
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Trugilo KP, Cebinelli GCM, Castilha EP, da Silva MR, Berti FCB, de Oliveira KB. The role of transforming growth factor β in cervical carcinogenesis. Cytokine Growth Factor Rev 2024; 80:12-23. [PMID: 39482191 DOI: 10.1016/j.cytogfr.2024.10.006] [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: 08/23/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 11/03/2024]
Abstract
Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer.
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Affiliation(s)
- Kleber Paiva Trugilo
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
| | | | - Eliza Pizarro Castilha
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
| | - Mariane Ricciardi da Silva
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
| | | | - Karen Brajão de Oliveira
- Laboratory of Molecular Genetics and Immunology, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, State University of Londrina, PR 86057-970, Brazil.
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3
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Gnanagurusamy J, Krishnamoorthy S, Muthusami S. Transforming growth factor-β micro-environment mediated immune cell functions in cervical cancer. Int Immunopharmacol 2024; 140:112837. [PMID: 39111147 DOI: 10.1016/j.intimp.2024.112837] [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: 02/19/2024] [Revised: 07/02/2024] [Accepted: 07/28/2024] [Indexed: 09/01/2024]
Abstract
Propensity to develop cervical cancer (CC) in human papilloma virus (HPV) infected individual could potentially involve the impaired immune functioning. Several stages of HPV surveillance by immune cells in tumor micro-environment (TME) is regulated mainly by transforming growth factor-beta (TGF-β) and is crucial for the establishment of CC. The role of TGF-β in the initiation and progression of CC is very complex and involve different suppressor of mothers against decapentaplegic homolog (SMAD) dependent and SMAD independent signaling mechanism(s). This review summarizes the handling of HPV by immune cells such as T lymphocytes, B lymphocytes, natural killer cells (NK), dendritic cells (DC), monocytes, macrophages, myeloid derived suppressor cells (MDSC) and their regulation by TGF-β. The hijack mechanisms adapted by HPV to evade this surveillance process is discussed. Biomarkers indicating the stages of CC and immune checkpoints that can be targeted for improved outcome are included for immune-based theragnostics. This review also addresses the direct actions of TGF-β on CC cells and tumor/immune cell interactions. Therapies focused on targeting TGF-β using small molecule inhibitors, monoclonal antibodies and TGF-β chimeric antigen receptor (CAR)T cells are collated to understand the current strategies related to TGF-β in the management of CC.
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Affiliation(s)
- Jayapradha Gnanagurusamy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | - Sneha Krishnamoorthy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | - Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India; Centre for Cancer Research, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India.
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4
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Gong M, Shen F, Li Y, Ming L, Hong L. MLK4 as an immune marker and its correlation with immune infiltration in Cervical squamous cell carcinoma and endocervical adenocarcinoma(CESC). PLoS One 2023; 18:e0290462. [PMID: 37594950 PMCID: PMC10437903 DOI: 10.1371/journal.pone.0290462] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 08/09/2023] [Indexed: 08/20/2023] Open
Abstract
Mixed pedigree kinase 4 (MLK4) is a member of the serine/threonine kinases mixed pedigree kinase (MLKs) family. Few reports on immune-related targets in Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and the role of MLK4 in cervical cancer remains to be studied. The expression of MLK4 in CESC was analyzed by TCGA database containing 306 CESC tissues and 3 peritumoral tissue samples, and the effect of MLK4 on immune invasion was evaluated using the Deseq2 package(Benjamini-Hochberg corrected p-value < 0.05 and log2 fold change ≥|2|). Tissue microarray was used to verify the expression of MLK4 in CESC patients, and it was found that MLK4 was significantly overexpressed in CESC, and significantly correlated with WHO grade. Multiple analysis algorithms revealed that the high expression of MLK4 was negatively correlated with immune cell infiltration in CESC. Analysis showed that MLK4 expression was negatively correlated with the infiltration of various immune cells including CD8+T cells, and MLK4 mRNA expression was positively correlated with immune checkpoints PD-L1,CTLA4, LAG3, and negatively correlated with immune promotion genes CD86 and CD80. Furthermore, vitro assays were performed to investigate the biological characteristics of MLK4 in C33A cells. The EDU and transwell assays demonstrated that the decrease in MLK4 expression in C33A cells resulted in a decrease in cell proliferation and invasion. The silencing of MLK4 resulted in a significant increase in the expression of inflammatory cytokines IL-1β(p<0.05), TNF-α(p<0.01), and IL-6 (p<0.05). The results of cell assays indicate that knocking down MLK4 would inhibit the expression of established biochemical markers CEA, AFP and HCG. Hence, it is plausible that MLK4 could potentially exert a significant influence on the development and progression of Cervical cancer.
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Affiliation(s)
- Meng Gong
- Gynecology Department, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fujin Shen
- Gynecology Department, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Li
- Gynecology Department, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lei Ming
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Hong
- Gynecology Department, Renmin Hospital of Wuhan University, Wuhan, China
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5
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Blay Mensah LB, Ken-Amoah S, Essuman MA, Anane-Fenin B, Agbeno EK, Eliason S, Essien-Baidoo S. Cervical Microbiota Influences Cytokine Diversity in Cervical Intraepithelial Neoplasia among Rural Women in the Akyemansa District of Ghana. BIOMED RESEARCH INTERNATIONAL 2023; 2023:5129709. [PMID: 37635942 PMCID: PMC10450155 DOI: 10.1155/2023/5129709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/03/2023] [Accepted: 07/31/2023] [Indexed: 08/29/2023]
Abstract
Background In recent times, cervical dysbiosis which mostly causes and aggravates infections is highlighted for its role in immune modulation in cervical dysplasia, which promotes the shifting of Th1 phenotype immunity to Th2 phenotype immunity. This study therefore estimated and compared the levels of circulatory IL-4, IL-6, IL-10, TNF-α, and IFN-γ cytokines among adult women identified to have different grades of cervical intraepithelial neoplasia (CIN) and with cervicovaginal infection. Methods A total of 157 participants were recruited from the Akyemansa District of Ghana, and cervical swabs and blood samples were taken. The Pap smear test, microbiological culture, and ELISA were employed for cytology analysis, bacteria isolation, and identification and estimation of IL-4, IL-6, IL-10, TNF-α, and IFN-γ cytokines, respectively. Results Overall, 14/157 (8.9%) had CIN with 7.6% having CIN 1 and 1.3% having CIN 2. The main predictor for CIN was age above 46 years (OR 11.16, 95% CI: 2.4-51.8). Bacterial vaginosis (p = 0.003) and Candida infection (p = 0.012) were significantly higher in CIN. Again, Staphylococcus aureus (60% vs. 17.6%, p = 0.005), Citrobacter sp. (40.0% vs. 13.2%, p = 0.017), and Morganella morganii (40.0% vs. 4.4%, p = 0.002) isolates were significantly higher in CIN-positive participants. IL-10 and TNF-α concentrations were elevated in participants with CIN 1+ (TNF-α NIL vs. CIN 1+ only, p < 0.05) while IL-6 was decreased among participants with CIN 1+. In the presence of vaginal infection, TNF-α decreased among CIN 1+ participants while IL-10 remained elevated. Conclusion The findings of this study suggest that cervical dysbiosis causes immune suppression, which creates a suitable microenvironment for the development of CIN.
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Affiliation(s)
- Loretta Betty Blay Mensah
- Department of Microbiology and Immunology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Sebastian Ken-Amoah
- Department of Obstetrics and Gynaecology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Mainprice Akuoko Essuman
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Betty Anane-Fenin
- Department of Obstetrics and Gynaecology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Evans Kofi Agbeno
- Department of Obstetrics and Gynaecology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Sebastian Eliason
- Department of Community Medicine, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Samuel Essien-Baidoo
- Department of Microbiology and Immunology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
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Gutierrez-Silerio GY, Bueno-Topete MR, Vega-Magaña AN, Bastidas-Ramirez BE, Gutierrez-Franco J, Escarra-Senmarti M, Pedraza-Brindis EJ, Peña-Rodriguez M, Ramos-Marquez ME, Delgado-Rizo V, Banu N, Alejandre-Gonzalez AG, Fafutis-Morris M, Haramati J, Del Toro-Arreola S. Non-fitness status of peripheral NK cells defined by decreased NKp30 and perforin, and increased soluble B7H6, in cervical cancer patients. Immunology 2023; 168:538-553. [PMID: 36271832 DOI: 10.1111/imm.13593] [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: 06/21/2022] [Accepted: 10/18/2022] [Indexed: 11/29/2022] Open
Abstract
The NKp30 receptor is one of the three natural cytotoxic receptors reported in NK cells. This receptor is codified by the NCR3 gene, which encodes three isoforms, a consequence of the alternative splicing of exon 4. A greater expression of the three isoforms (A, B, and C), along with low levels of the NKp30 ligand B7H6, has been reported as a positive prognostic factor in different cancer types. Here, in patients with cervical cancer and precursor lesions, we report an altered immune-phenotype, characterized by non-fitness markers, that correlated with increased disease stage, from CIN 1 to FIGO IV. While overall NK cell numbers increased, loss of NKp30+ NK cells, especially in the CD56dim subpopulation, was found. Perforin levels were decreased in these cells. Decreased expression of the NKp30 C isoform and overexpression of soluble B7H6 was found in cervical cancer patients when compared against healthy subjects. PBMCs from healthy subjects downregulated NKp30 isoforms after co-culture with B7H6-expressing tumour cells. Taken together, these findings describe a unique down-modulation or non-fitness status of the immune response in cervical cancer, the understanding of which will be important for the design of novel immunotherapies against this disease.
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Affiliation(s)
- Gloria Yareli Gutierrez-Silerio
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico.,Laboratorio de Endocrinología y Nutrición, Departamento de Investigación Biomédica, Facultad de Medicina, Universidad Autónoma de Querétaro, Querétaro, Mexico
| | - Miriam Ruth Bueno-Topete
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Alejandra Natali Vega-Magaña
- Instituto de Investigación en Ciencias Biomédicas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico.,Laboratorio de Diagnóstico de Enfermedades Emergentes y Reemergentes, Departamento de Microbiología y Patología, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Blanca Estela Bastidas-Ramirez
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Jorge Gutierrez-Franco
- Unidad Académica de Ciencias Químico Biológicas y Farmacéuticas, Universidad Autónoma de Nayarit, Tepic, Mexico
| | | | - Eliza Julia Pedraza-Brindis
- Departamento Academia de Aparatos y Sistemas I, Unidad Académica de Ciencias de la Salud, Universidad Autónoma de Guadalajara, Guadalajara, Mexico
| | - Marcela Peña-Rodriguez
- Laboratorio de Diagnóstico de Enfermedades Emergentes y Reemergentes, Departamento de Microbiología y Patología, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Martha Eloisa Ramos-Marquez
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Vidal Delgado-Rizo
- Centro de Investigación en Inmunología y Dermatología, Departamento de Fisiología, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Nehla Banu
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico.,Division of Infectious Diseases, Allergy and Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Alan Guillermo Alejandre-Gonzalez
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Mary Fafutis-Morris
- Centro de Investigación en Inmunología y Dermatología, Departamento de Fisiología, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
| | - Jesse Haramati
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Guadalajara, Mexico
| | - Susana Del Toro-Arreola
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico.,Laboratorio de Inmunología, Departamento de Fisiología, CUCS, Universidad de Guadalajara, Guadalajara, Mexico
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7
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Hollis AR. Management of equine sarcoids. Vet J 2023; 291:105926. [PMID: 36334801 DOI: 10.1016/j.tvjl.2022.105926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 10/19/2022] [Accepted: 10/29/2022] [Indexed: 12/12/2022]
Abstract
Sarcoids are the most common cutaneous neoplasm of the horse, arising as a result of a neoplastic proliferation of fibroblasts associated with infection with bovine papillomavirus, most notably types 1 and 2. Although they do not metastasise, they are locally invasive and aggressive, and can lead to important welfare concerns, interfere with tack and therefore impede athleticism, and undoubtedly lead to a reduction in the value of affected horses. This review discusses the evidence behind the most commonly used treatments for equine sarcoids. The most commonly used treatments are discussed. No one treatment is universally successful, and there are many treatments with varying level of scientific evaluation and reported success rates.
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Affiliation(s)
- Anna R Hollis
- Cambridge Equine Hospital, Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
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8
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Aghbash PS, Hemmat N, Fathi H, Baghi HB. Monoclonal antibodies in cervical malignancy-related HPV. Front Oncol 2022; 12:904790. [PMID: 36276117 PMCID: PMC9582116 DOI: 10.3389/fonc.2022.904790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 09/20/2022] [Indexed: 11/20/2022] Open
Abstract
Despite many efforts to treat HPV infection, cervical cancer survival is still poor for several reasons, including resistance to chemotherapy and relapse. Numerous treatments such as surgery, radiation therapy, immune cell-based therapies, siRNA combined with various drugs, and immunotherapy are being studied and performed to provide the best treatment. Depending on the stage and size of the tumor, methods such as radical hysterectomy, pelvic lymphadenectomy, or chemotherapy can be utilized to treat cervical cancer. While accepted, these treatments lead to interruptions in cellular pathways and immune system homeostasis. In addition to a low survival rate, cervical neoplasm incidence has been rising significantly. However, new strategies have been proposed to increase patient survival while reducing the toxicity of chemotherapy, including targeted therapy and monoclonal antibodies. In this article, we discuss the types and potential therapeutic roles of monoclonal antibodies in cervical cancer.
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Affiliation(s)
- Parisa Shiri Aghbash
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamidreza Fathi
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tabriz, Iran
| | - Hossein Bannazadeh Baghi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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9
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Sherer MV, Kotha NV, Williamson C, Mayadev J. Advances in immunotherapy for cervical cancer: recent developments and future directions. Int J Gynecol Cancer 2022; 32:281-287. [PMID: 35256414 DOI: 10.1136/ijgc-2021-002492] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/14/2021] [Indexed: 01/01/2023] Open
Abstract
There is an unmet need for novel therapies to improve clinical outcomes for patients with locally advanced, recurrent, or metastatic cervical cancer. Most cases of cervical cancer are driven by infection with human papillomavirus (HPV), which uses multiple mechanisms to avoid immune surveillance. Several classes of agents have been developed that seek to activate the immune system in order to overcome this resistance and improve treatment outcomes. These include immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and antibody-drug conjugates. Here, we review the immune landscape of cervical cancer and the growing clinical data regarding the use of immunotherapy. Checkpoint inhibitors are the best studied treatments, with encouraging phase II studies available in the definitive setting and recently published phase III data defining a new standard of care for patients with recurrent or metastatic disease. Vaccines and engineered T cells are generally in earlier phases of development but use unique mechanisms of immune activation. It is possible that combination of immunotherapy, with either conventional systemic therapy or multiple immunomodulatory agents, may provide further benefit. We also discuss possible synergies between immunotherapy and radiation therapy, which is frequently used in the management of cervical cancer. Ultimately, immunotherapy represents an emerging treatment option for patients with cervical cancer. It is an appropriate component of first-line treatment in the recurrent or metastatic setting and may soon be incorporated into definitive management of locally advanced disease.
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Affiliation(s)
- Michael Vincent Sherer
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA
| | - Nikhil V Kotha
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA
| | - Casey Williamson
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA
| | - Jyoti Mayadev
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA
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10
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Lathika AS, Lakshmi S, Ramdas PT, Kumar A, Mathews S, Joseph J, Mathew A, James FV. Programmed Death Ligand 1 (PD-L1) Expression in Cervical Cancer. INDIAN JOURNAL OF GYNECOLOGIC ONCOLOGY 2021. [DOI: 10.1007/s40944-021-00584-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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11
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Galicia-Carmona T, Arango-Bravo E, Serrano-Olvera JA, Flores-de La Torre C, Cruz-Esquivel I, Villalobos-Valencia R, Morán-Mendoza A, Castro-Eguiluz D, Cetina-Pérez L. ADXS11-001 LM-LLO as specific immunotherapy in cervical cancer. Hum Vaccin Immunother 2021; 17:2617-2625. [PMID: 33793380 DOI: 10.1080/21645515.2021.1893036] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Human papillomavirus (HPV) infection is a well-known cause of cervical cancer. Therapeutic cancer vaccines are part of the current therapeutic options for HPV-associated cancers. Axalimogen filolisbac (ADXS11-001) is an immunotherapy based on live attenuated Listeria monocytogenes-listeriolysin O (Lm-LLO), designed by biological engineering to secrete an antigen-adjuvant fusion protein, composed of a truncated fragment of LLO fused to HPV. The proposed mechanism of action is that Lm-based vectors infect antigen-presenting cells (APC) and secrete HPV-LLO fusion proteins within the APC cytoplasm, these proteins are processed and presented to cytotoxic T lymphocytes (CTL), thus generating a new population of CTLs specific to HPV antigens. These HPV-specific CTLs destroy HPV infected cells. ADXS11-001 has demonstrated safety results in phase I-II studies in women with cervical cancer and is being assessed in clinical trials in patients with HPV-positive anal canal and head and neck cancers.
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Affiliation(s)
- Tatiana Galicia-Carmona
- Department of Clinical Research, Instituto Nacional De Cancerología, Mexico City, Mexico.,Department of Medical Oncology, Instituto Nacional De Cancerología, Mexico City, Mexico
| | - Eder Arango-Bravo
- Department of Clinical Research, Instituto Nacional De Cancerología, Mexico City, Mexico.,Department of Medical Oncology, Instituto Nacional De Cancerología, Mexico City, Mexico
| | | | - Celia Flores-de La Torre
- Department of Medical Oncology, Centro Estatal De Oncología Campeche INDESALUD, Campeche, Mexico
| | - Ivan Cruz-Esquivel
- Department of Surgical Oncology, Centro Estatal De Oncología Campeche INDESALUD, Campeche, Mexico
| | - Ricardo Villalobos-Valencia
- Oncology Hospital, Centro Médico Siglo XXI, Instituto Mexicano Del Seguro Social (IMSS), Mexico City, Mexico
| | - Andrés Morán-Mendoza
- Department of Oncology, UMAE Hospital Ginecoobstetricia, Centro Médico Nacional De Occidente, Instituto Mexicano Del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | | | - Lucely Cetina-Pérez
- Department of Clinical Research, Instituto Nacional De Cancerología, Mexico City, Mexico.,Department of Medical Oncology, Instituto Nacional De Cancerología, Mexico City, Mexico
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12
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Qiu Q, Zhou Q, Luo A, Li X, Li K, Li W, Yu M, Amanullah M, Lu B, Lu W, Liu P, Lu Y. Integrated analysis of virus and host transcriptomes in cervical cancer in Asian and Western populations. Genomics 2021; 113:1554-1564. [PMID: 33785400 DOI: 10.1016/j.ygeno.2021.03.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 03/09/2021] [Accepted: 03/26/2021] [Indexed: 12/31/2022]
Abstract
Race may influence vulnerability to HPV variants in viral infection and perisistence. Integrated analysis of the virus and host transcriptomes from different populations provides an unprecedented opportunity to understand these racial disparities in the prevalence of HPV and cervical cancers. We performed RNA-Seq analysis of 90 tumors and 39 adjacent normal tissues from cervical cancer patients at Zhejiang University (ZJU) in China, and conducted a comparative analysis with RNA-Seq data of 286 cervical cancers from TCGA. We found a modestly higher rate of HPV positives and HPV integrations in TCGA than in ZJU. In addition to LINC00393 and HSPB3 as new common integration hotspots in both cohorts, we found new hotspots such as SH2D3C and CASC8 in TCGA, and SCGB1A1 and ABCA1 in ZJU. We described the first, to our knowledge, virus-transcriptome-based classification of cervical cancer associated with clinical outcome. Particularly, patients with expressed E5 performed better than those without E5 expression. However, the constituents of these virus-transcriptome-based tumor subtypes differ dramatically between the two cohorts. We further characterized the immune infiltration landscapes between different HPV statuses and revealed significantly elevated levels of regulatory T cells and M0 macrophages in HPV positive tumors, which were associated with poor prognosis. These findings increase our understanding of the racial disparities in the prevalence of HPV and its associated cervical cancers between the two cohorts, and also have important implications in the classification of tumor subtypes, prognosis, and anti-cancer immunotherapy in cervical cancer.
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Affiliation(s)
- Qiongzi Qiu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China
| | - Qing Zhou
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China
| | - Aoran Luo
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China
| | - Xufan Li
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
| | - Kezhen Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wenfeng Li
- Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Mengqian Yu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China
| | - Md Amanullah
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China
| | - Bingjian Lu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China
| | - Weiguo Lu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China.
| | - Pengyuan Liu
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China; Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Yan Lu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310002, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China.
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13
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Wang Y, He M, Zhang G, Cao K, Yang M, Zhang H, Liu H. The immune landscape during the tumorigenesis of cervical cancer. Cancer Med 2021; 10:2380-2395. [PMID: 33694292 PMCID: PMC7982625 DOI: 10.1002/cam4.3833] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/20/2021] [Accepted: 02/21/2021] [Indexed: 12/20/2022] Open
Abstract
Objective Deciphering the determinants of the intralesional immune reaction in cervical carcinogenesis may be conducive to improving the understanding of the disease and then improve outcomes. Methods Public gene‐expression data and full clinical annotation were searched in Gene Expression Omnibus in the joint analysis of the array‐based four eligible cohorts. The infiltrating estimation was quantified using microenvironment cell populations‐counter algorithm and absolute‐mode CIBERSORT and verified by flow cytometry analysis. An unsupervised classification on immune genes strongly associated with progression, designated by linear mixed‐effects regression. We determined immune response and signaling features of the different developmental stages and immune phenotypes by functional annotation and systematically correlated the expression of immune checkpoints with cell‐infiltrating characteristics. Results We identified the lesion‐intrinsic immunosuppression mechanism was triggered at precancerous stages, such as genome instability and mutation, aerobic glycolysis, activation of proto‐oncogene pathways and so forth. Predominant innate and adoptive cells were increasing from normalcy to cancer (B cell, total T cell, regulatory T cells [Tregs], monocytes, neutrophils, and M2‐like macrophages) together with the decrease of CD4+ T cell and CD8+ T cell through the development of cervical cancer. Immune escape initiated on the expression of immunosuppressive molecules from high‐grade squamous intraepithelial lesions (HSIL) and culminated in squamous cell carcinoma (SCC). Of note, the expression of immune checkpoints was escalated in the immune‐hot and immune‐warm phenotype largely encompassed by HSIL and SCC under the stress of both activated and suppressive immune responses. Conclusions Immune surveillance is unleashing from low‐grade squamous intraepithelial lesions onwards and immune‐suppression mechanisms are triggered in HSIL. Thorough knowledge of the immune changing pattern during cervical tumorigenesis contributes to finding the potential therapeutic targets to susceptive patients towards immune checkpoints inhibitors.
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Affiliation(s)
- Yiying Wang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Mengdi He
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Guodong Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Kankan Cao
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Moran Yang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Hongwei Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Haiou Liu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
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14
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Carrero YN, Callejas DE, Mosquera JA. In situ immunopathological events in human cervical intraepithelial neoplasia and cervical cancer: Review. Transl Oncol 2021; 14:101058. [PMID: 33677234 PMCID: PMC7937982 DOI: 10.1016/j.tranon.2021.101058] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022] Open
Abstract
Neoplasia of the cervix represents one of the most common cancers in women. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. The in-situ expression of several cytokines by uterine epithelial cells and by infiltrating leukocytes occurs during the cervical intraepithelial neoplasia and cervical cancer. Some of these cytokines can prevent and others can induce the progression of the neoplasm. The infiltrating leukocytes also produce cytokines and growth factors relate to angiogenesis, chemotaxis, and apoptosis capable of modulating the dysplasia progression. In this review we analyzed several interleukins with an inductive effect or blocking effect on the neoplastic progression. We also analyze the genetic polymorphism of some cytokines and their relationship with the risk of developing cervical neoplasia. In addition, we describe the leukocyte cells that infiltrate the cervical uterine tissue during the neoplasia and their effects on neoplasia progression.
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Affiliation(s)
- Yenddy N Carrero
- Facultad de Ciencias de la Salud. Carrera de Medicina, Universidad Técnica de Ambato, Ambato, Ecuador.
| | - Diana E Callejas
- Departamento de Ciencias Biológicas, Facultad de Ciencias de la Salud, Universidad Técnica de Manabí, Portoviejo, Ecuador.
| | - Jesús A Mosquera
- Instituto de Investigaciones Clínicas Dr. Américo Negrette. Facultad de Medicina, Universidad del Zulia. Maracaibo, Venezuela.
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15
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Lin W, Zhang HL, Niu ZY, Wang Z, Kong Y, Yang XS, Yuan F. The disease stage-associated imbalance of Th1/Th2 and Th17/Treg in uterine cervical cancer patients and their recovery with the reduction of tumor burden. BMC WOMENS HEALTH 2020; 20:126. [PMID: 32552719 PMCID: PMC7301485 DOI: 10.1186/s12905-020-00972-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 05/10/2020] [Indexed: 01/21/2023]
Abstract
Background Nearly all uterine cervical cancer (UCC) cases result from human papillomavirus (HPV) infection. After high-risk HPV infection, most HPV infections are naturally cleared by humoral and cell-mediated immune responses. Thus, cervical lesions of only few patients progress into cervical cancer via cervical intraepithelial neoplasia (CIN) and lead to persistent oncogenic HPV infection. This suggests that immunoregulation plays an instrumental role in the carcinogenesis. However, there was a few studies on the relation between the immunologic dissonance and clinical characteristics of UCC patients. Method We examined the related immune cells (Th1, Th2, Th17, and Treg cells) by flow cytometric analysis and analyzed their relations with UCC stages, tumor size, differentiation, histology type, lymph node metastases, and vasoinvasion. Next, we quantified the Th1, Th2, Th17, and Treg cells before and after the operation both in UCC and CIN patients. Results When compared with stage I patients, decreased levels of circulating Th1 cells and elevated levels of Th2, Th17, and Treg cells were detected in stage II patients. In addition, the imbalance of Th1/Th2 and Th17/Treg cells was related to the tumor size, lymph node metastases, and vasoinvasion. We found that immunological cell levels normalized after the operations. In general, immunological cell levels in CIN patients normalized sooner than in UCC patients. Conclusions Our findings suggested that peripheral immunological cell levels reflect the patient’s condition.
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Affiliation(s)
- Wei Lin
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Hua-Ling Zhang
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Zhao-Yuan Niu
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Zhen Wang
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Yan Kong
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xing-Sheng Yang
- Department of Obstetrics and Gynecology, Qi Lu Hospital of Shandong University, Jinan, People's Republic of China.
| | - Fang Yuan
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China.
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16
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Barra F, Della Corte L, Noberasco G, Foreste V, Riemma G, Di Filippo C, Bifulco G, Orsi A, Icardi G, Ferrero S. Advances in therapeutic vaccines for treating human papillomavirus-related cervical intraepithelial neoplasia. J Obstet Gynaecol Res 2020; 46:989-1006. [PMID: 32390320 DOI: 10.1111/jog.14276] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 03/23/2020] [Accepted: 04/12/2020] [Indexed: 12/29/2022]
Abstract
AIM Human papillomavirus (HPV) is the etiologic agent of the majority of cervical intraepithelial lesions (CIN) and cervical cancers. While prophylactic HPV vaccines prevent infections from the main high-risk HPV types associated with cervical cancer, alternative nonsurgical and nonablative therapeutics to treat HPV infection and preinvasive HPV diseases have been experimentally investigated. Therapeutic vaccines are an emerging investigational strategy. This review aims to introduce the results of the main clinical trials on the use of therapeutic vaccines for treating HPV infection and -related CIN, reporting the ongoing studies on this field. METHODS Data research was conducted using MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library querying for all articles related to therapeutic vaccines for the treatment of HPV-related CIN. Selection criteria included randomized clinical trials, nonrandomized controlled studies and review articles. RESULTS Preliminary data are available on the evaluation of therapeutic vaccines for treating cervical HPV infections and CIN. Despite having in vitro demonstrated to obtain humoral and cytotoxic responses, therapeutic vaccines have not yet clinically demonstrated consistent success; moreover, each class of therapeutic vaccines has advantages and limitations. Early clinical data are available in the literature for these compounds, except for MVA E2, which reached the phase III clinical trial status, obtaining positive clinical outcomes. CONCLUSION Despite promising results, to date many obstacles are still present before hypothesize an introduction in the clinical practice within the next years. Further studies will draw a definitive conclusion on the role of therapeutic vaccines in this setting.
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Affiliation(s)
- Fabio Barra
- Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giovanni Noberasco
- Department of Health Sciences (DiSSal), University of Genoa, Genoa, Italy
| | - Virginia Foreste
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gaetano Riemma
- Department of Woman, Child and General and Specialized Surgery, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Claudia Di Filippo
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giuseppe Bifulco
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Andrea Orsi
- Department of Health Sciences (DiSSal), University of Genoa, Genoa, Italy.,HygieneUnit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Giancarlo Icardi
- Department of Health Sciences (DiSSal), University of Genoa, Genoa, Italy.,HygieneUnit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Simone Ferrero
- Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
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17
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Pfaffenzeller MS, Franciosi MLM, Cardoso AM. Purinergic signaling and tumor microenvironment in cervical Cancer. Purinergic Signal 2020; 16:123-135. [PMID: 32170538 PMCID: PMC7166227 DOI: 10.1007/s11302-020-09693-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer is the fourth most common type of cancer incidence in the world female population, and it has become a public health problem worldwide. Several factors are involved in this type of cancer, including intrinsic factors related to the inflammatory process, such as extracellular nucleotides and adenosine-components of the purinergic system. The present review focuses on the role of the purinergic system in cervical cancer, especially regarding the interaction of extracellular nucleotides with their respective receptors expressed in the tumor microenvironment of cervical cancer and their role in the host immune response. The high concentrations of extracellular nucleotides in the tumor microenvironment of cervical cancer interfere in the regulation, proliferation, differentiation, and apoptosis of cancer cells of the uterine cervix through different P1 and P2 receptor subtypes. Such diverse cellular processes that are mediated by adenosine triphosphate and adenosine across the tumor microenvironment and that also have effects on host immune defense will be reviewed here in detail.
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Affiliation(s)
| | | | - Andréia Machado Cardoso
- Academic Coordination, Medicine, Campus Chapecó, Federal University of Fronteira Sul, Chapecó, SC Brazil
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18
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Venancio PA, Consolaro MEL, Derchain SF, Boccardo E, Villa LL, Maria-Engler SS, Campa A, Discacciati MG. Indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase expression in HPV infection, SILs, and cervical cancer. Cancer Cytopathol 2019; 127:586-597. [PMID: 31412167 DOI: 10.1002/cncy.22172] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 07/21/2019] [Accepted: 07/22/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Human papillomavirus (HPV) infection is the central factor for cervical cancer, whereas epithelial immune mechanisms contribute to the progression of HPV infection and its associated lesions. The authors evaluated the expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) in cervicovaginal samples from women with normal cervical epithelium or with different degrees of squamous intraepithelial lesions (SILs) and cervical cancer. METHODS IDO expression was analyzed by immunocytochemistry in liquid-based cytology samples from 165 women, of whom 42 had cervical changes subclassified as low-grade SIL (n = 6), high-grade SIL (n = 30), or squamous cell carcinoma (SCC) (n = 6), and 123 had negative Papanicolaou smears. IDO and TDO expression also were analyzed by immunohistochemistry, and HPV and other genital pathogens were evaluated by polymerase chain reaction analysis. RESULTS Low IDO expression was observed in normal cervical epithelium irrespective of HPV status. Increased numbers of IDO-positive squamous cells and IDO-positive leukocytes were observed in women with SIL or SCC. TDO expression was detected in leukocytes infiltrating the stroma around intraepithelial or invasive cervical lesions. Higher IDO levels were detected in organotypic epithelial cultures established from keratinocytes transduced with the HPV16 E6/E7 oncoproteins. CONCLUSIONS The upregulation of IDO expression in leukocytes and squamous cells in HPV-associated SIL and SCC suggests that immunosuppressive mechanisms involving tryptophan metabolism may have a role in cervical carcinogenesis. Although previous studies have suggested the role of IDO in HPV pathogenesis, this is the first evidence of TDO involvement in the process. Furthermore, the current data emphasize the role of leukocytes, especially neutrophil-like cells, as an IDO source.
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Affiliation(s)
- Paloma Almeida Venancio
- Department of Clinical Analysis and Toxicology, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Sophie Françoise Derchain
- Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil
| | - Enrique Boccardo
- Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Luisa Lina Villa
- Department of Radiology and Oncology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Silvya Stuchi Maria-Engler
- Department of Clinical Analysis and Toxicology, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana Campa
- Department of Clinical Analysis and Toxicology, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Michelle Garcia Discacciati
- Department of Clinical Analysis and Toxicology, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.,Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, Campinas, Sao Paulo, Brazil
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19
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The Host-Microbe Interplay in Human Papillomavirus-Induced Carcinogenesis. Microorganisms 2019; 7:microorganisms7070199. [PMID: 31337018 PMCID: PMC6680694 DOI: 10.3390/microorganisms7070199] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
Every year nearly half a million new cases of cervix cancer are diagnosed worldwide, making this malignancy the fourth commonest cancer in women. In 2018, more than 270,000 women died of cervix cancer globally with 85% of them being from developing countries. The majority of these cancers are caused by the infection with carcinogenic strains of human papillomavirus (HPV), which is also causally implicated in the development of other malignancies, including cancer of the anus, penis cancer and head and neck cancer. HPV is by far the most common sexually transmitted infection worldwide, however, most infected people do not develop cancer and do not even have a persistent infection. The development of highly effective HPV vaccines against most common high-risk HPV strains is a great medical achievement of the 21st century that could prevent up to 90% of cervix cancers. In this article, we review the current understanding of the balanced virus-host interaction that can lead to either virus elimination or the establishment of persistent infection and ultimately malignant transformation. We also highlight the influence of certain factors inherent to the host, including the immune status, genetic variants and the coexistence of other microbe infections and microbiome composition in the dynamic of HPV infection induced carcinogenesis.
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20
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Human Papilloma Virus and Chlamydia trachomatis: Casual Acquaintances or Partners in Crime? CURRENT CLINICAL MICROBIOLOGY REPORTS 2019. [DOI: 10.1007/s40588-019-00117-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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21
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Bacolod MD, Barany F, Pilones K, Fisher PB, de Castro RJ. Pathways- and epigenetic-based assessment of relative immune infiltration in various types of solid tumors. Adv Cancer Res 2019; 142:107-143. [PMID: 30885360 DOI: 10.1016/bs.acr.2019.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Recent clinical studies document the power of immunotherapy in treating subsets of patients with advanced cancers. In this context and with multiple cancer immunotherapeutics already evaluated in the clinic and a large number in various stages of clinical trials, it is imperative to comprehensively examine genomics data to better comprehend the role of immunity in different cancers in predicting response to therapy and in directing appropriate therapies. The approach we chose is to scrutinize the pathways and epigenetic factors predicted to drive immune infiltration in different cancer types using publicly available TCGA transcriptional and methylation datasets, along with accompanying clinico-pathological data. We observed that the relative activation of T cells and other immune signaling pathways differs across cancer types. For example, pathways related to activation and proliferation of helper and cytotoxic T cells appear to be more highly enriched in kidney, skin, head and neck, and esophageal cancers compared to those of lung, colorectal, and liver or bile duct cancers. The activation of these immune-related pathways positively associated with prognosis in certain cancer types, most notably melanoma, head and neck, and cervical cancers. Integrated methylation and expression data (along with publicly available, ENCODE-generated histone ChIP Seq and DNAse hypersensitivity data) predict that epigenetic regulation is a primary factor driving transcriptional activation of a number of genes crucial to immunity in cancer, including T cell receptor genes (e.g., CD3D, CD3E), CTLA4, and GZMA. However, the extent to which epigenetic factors (primarily methylation at promoter regions) affect transcription of immune-related genes may vary across cancer types. For example, there is a high negative correlation between promoter CpG methylation and CD3D expression in renal and thyroid cancers, but not in brain tumors. The types of analyses we have undertaken provide insights into the relationships between immune modulation and cancer etiology and progression, offering clues into ways of therapeutically manipulating the immune system to promote immune recognition and immunotherapy.
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Affiliation(s)
- Manny D Bacolod
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States.
| | - Francis Barany
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States
| | - Karsten Pilones
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
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22
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Trugilo KP, Cebinelli GCM, Berti FCB, Okuyama NCM, Cezar-Dos-Santos F, Sena MM, Mangieri LFL, Watanabe MAE, de Oliveira KB. Polymorphisms in the TGFB1 signal peptide influence human papillomavirus infection and development of cervical lesions. Med Microbiol Immunol 2018; 208:49-58. [PMID: 30167873 DOI: 10.1007/s00430-018-0557-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 08/23/2018] [Indexed: 12/26/2022]
Abstract
The main purpose was to assess the effect of c.29C>T and c.74G>C polymorphisms in the TGFB1 signal peptide on HPV infection and development of cervical lesions. Cervical swabs and blood samples were obtained from 349 outpatient women, along with socio-demographic and sexual behavioral data. The study population was stratified by absence or presence of HPV DNA, as tested by PCR, as well as by lesion grade. TGFB1 signal peptide polymorphisms were genotyped using PCR-restriction fragment length polymorphism. HPV DNA was detected in 172 (49.3%) patients. c.74GC and the combined c.29CC+CT/c.74GC genotype were more frequent in infected patients (35.1 and 15.7%) than in uninfected women (6.2 and 14.7%). Accordingly, these genotypes were associated with a higher risk of HPV infection, with odds ratio and 95% confidence interval of 2.81 and 1.35-5.86 (P = 0.004) for c.74GC and 3.14 and 1.42-6.94 (P = 0.004) for the combined genotype, respectively. High-grade lesions were also 2.48 times more likely to occur in c.29CC patients than in c.29TT patients, with a 95% confidence interval of 1.01-6.08 (P = 0.047). The data demonstrate that c.74G>C and c.29C>T polymorphisms are significantly associated with risk of HPV infection and high-grade squamous intraepithelial lesions, respectively. Thus, TGFB1 signal peptide polymorphisms are potential susceptibility markers.
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Affiliation(s)
- Kleber Paiva Trugilo
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | | | - Fernanda Costa Brandão Berti
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Nádia Calvo Martins Okuyama
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Fernando Cezar-Dos-Santos
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Michelle Mota Sena
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Luis Fernando Lásaro Mangieri
- Department of Gynecology and Obstetrics, Health Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Maria Angelica Ehara Watanabe
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Karen Brajão de Oliveira
- Department of Pathological Science, Biological Science Center, State University of Londrina, Londrina, Paraná, Brazil.
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Ao C, Zeng K. The role of regulatory T cells in pathogenesis and therapy of human papillomavirus-related diseases, especially in cancer. INFECTION GENETICS AND EVOLUTION 2018; 65:406-413. [PMID: 30172014 DOI: 10.1016/j.meegid.2018.08.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/13/2018] [Accepted: 08/15/2018] [Indexed: 12/19/2022]
Abstract
Human papillomavirus (HPV) is the most common sexually transmitted agent in the world. It can cause condyloma acuminatum, anogenital malignancies, and head and neck cancers. The host immune responses to HPV involve multiple cell types that have regulatory functions, and HPV-mediated changes to regulatory T cells (Tregs) in both the local lesion tissues and the circulatory system of patients have received considerable attention. The role of Tregs in HPV infections ranges from suppression of effector T cell (Teff) responses to protection of tissues from immune-mediated injury in different anatomic subsites. In this review, we explore the influence of Tregs in the immunopathology of HPV-related diseases and therapies targeting Tregs as novel approaches against HPV.
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Affiliation(s)
- Chunping Ao
- Department of Dermatology and Venereology, Nanfang hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kang Zeng
- Department of Dermatology and Venereology, Nanfang hospital, Southern Medical University, Guangzhou, 510515, China.
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24
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Ma C, Zhang W, Wu Q, Liu Y, Wang C, Lao G, Yang L, Liu P. Identification of a microRNA signature associated with survivability in cervical squamous cell carcinoma. PLoS One 2018. [PMID: 29513728 PMCID: PMC5841789 DOI: 10.1371/journal.pone.0193625] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background The aim of this study is to find the potential miRNA expression signature capable of predicting survival time for cervical squamous cell carcinoma (CSCC) patients. Methods The expression of 332 miRNAs was measured in 131 (Training cohort) and 130 (Validation cohort) patients with CSCC in the Cancer Genome Atlas (TCGA) data portal. The miRNA expression signature was identified by Cox Proportion Hazard regression model to the Training data set, and subsequently validated in an independent Validation set. Kaplan-Meier curves and the receiver operating characteristic analyses of 5 years were used to access the overall survival of miRNA signature. MiRNA signature-gene target analysis was performed, followed by the construction of the regulatory network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to explore the function of target genes of miRNA signature. Results A 2-miRNA expression signature of hsa-mir-642a and hsa-mir-378c associated with survivability was identified in CSCC. Both of them had a significant diagnostic and prognostic value of patients with CSCC. A total of 345 miRNA signature-target pairs were obtained in the miRNA signature-gene target regulatory network, in which 316 genes were targets of has-mir-378c and has-mir-642a. Functional analysis of target genes showed that MAPK signaling pathway, VEGF signaling pathway and endocytosis were the significantly enriched signal pathways that covered most genes. Conclusions The 2-miRNA signature adds to the prognostic value of CSCC. In-depth interrogation of the 2-miRNAs will provide important biological insights that finding and developing novel molecularly prediction to improve prognosis for CSCC patients.
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Affiliation(s)
- Chengbin Ma
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Wenying Zhang
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Qiongwei Wu
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Yu Liu
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Chao Wang
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Guoying Lao
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Longtao Yang
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
| | - Ping Liu
- Department of Gynecology, Changning Maternity and Infant Health Hospital, Shanghai, China
- * E-mail:
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Das D, Sarkar B, Mukhopadhyay S, Banerjee C, Biswas Mondal S. An Altered Ratio of CD4+ And CD8+ T Lymphocytes in Cervical Cancer Tissues and Peripheral Blood – A Prognostic Clue? Asian Pac J Cancer Prev 2018; 19:471-478. [PMID: 29480666 PMCID: PMC5980936 DOI: 10.22034/apjcp.2018.19.2.471] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Background: Several studies have provided evidence of CD4+ and CD8+ lymphocyte infiltration in various malignancies with probable implications for prognosis. Cervical cancer accounts for a major part of the cancer burden in the developing world. Study of genetically and ethnically diverse Indian cervical cancer patients is necessary to assess effects on lymphocytic infiltration of tumour tissue. Methods: This observational study was conducted over a period of 12 months with selected cervical cancer patients meeting inclusion criteria. Samples of cervical cancer tissue and peripheral blood were obtained and tumour infiltration with CD4+ and CD8+ lymphocytes was noted. Cell numbers were quantified by flow-cytometry and proportions compared between tumour and peripheral blood samples. Results: Tumour infiltration was noted with both CD4+ (13.93±10.95) and CD8+ (19.5±12.05) lymphocyte subtypes. However, compared to peripheral blood, CD4+ cells were significantly less predominant in tumour tissue (p, 0.0013). There was a statistically significant (p, 0.0004) reversal of the ratio of CD4+ and CD8+ in the tumour tissue (0.68±0.39) compared to peripheral blood (1.5±0.66) with maximal alteration in higher stage disease. Conclusion: The study revealed that T lymphocyte infiltration of cervical cancer tissue occurs but the ratio of CD4+ to CD8+ subtypes is sifnificantly lower than in peripheral blood, especially with in advanced stages of disease. The clinical implications of such a reversal of CD4+ and CD8+ ratios is unknown, but might have prognostic significance.
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Affiliation(s)
- Diptimoy Das
- Department of Radiotherapy, Burdwan Medical College, Burdwan, India.
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26
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Mahantshetty U, Teni T, Naga P, Hotwani C, Umesh S, Kannan S, Hande V, Pawar S, Engineer R, Chopra S, Deodhar K, Maheshwari A, Gurram L, Gupta S, Shrivastava SK. Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study. Gynecol Oncol 2018; 148:299-304. [DOI: 10.1016/j.ygyno.2017.11.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/21/2017] [Accepted: 11/24/2017] [Indexed: 10/18/2022]
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27
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Brandt S. Immune response to bovine papillomavirus type 1 in equine sarcoid. Vet J 2016; 216:107-8. [DOI: 10.1016/j.tvjl.2016.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 07/18/2016] [Indexed: 11/16/2022]
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28
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Liu Z, Zhou H, Wang W, Fu YX, Zhu M. A novel dendritic cell targeting HPV16 E7 synthetic vaccine in combination with PD-L1 blockade elicits therapeutic antitumor immunity in mice. Oncoimmunology 2016; 5:e1147641. [PMID: 27471615 DOI: 10.1080/2162402x.2016.1147641] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 01/18/2016] [Accepted: 01/24/2016] [Indexed: 10/22/2022] Open
Abstract
Human papilliomavirus (HPV) oncogene E7, essential for the transformation and maintenance of the malignancy of cervical cancer cells, represents an ideal tumor-specific antigen for vaccine development. However, due to the poor immunogenicity of E7 protein, an effective therapeutic E7 vaccine is still lacking. Dendritic cells (DCs) are probably the most potent antigen presenting cells for the induction of cytotoxic T lymphocyte (CTL) response, which is crucial for tumor control. In this study, we tested whether targeting the E7 antigen to DCs in vivo would elicit therapeutic antitumor CTL response. We generated the DEC205-specific single-chain variable fragment (scFv) and E7 long peptide fusion protein [scFv(DEC205)-E7] based on the novel method of protein assembly we recently developed. This fusion protein vaccine demonstrated highly efficient DC-targeting in vivo and elicited much stronger protective CTL response than non-DC-targeting control vaccine in naive mice. Furthermore, the scFv(DEC205)-E7 vaccine showed significant therapeutic antitumor response in TC-1 tumor bearing mice. Importantly, PD-L1 blockade further improved the therapeutic effect of the scFv(DEC205)-E7 vaccine. Thus, the current study suggests an efficient strategy for cervical cancer immunotherapy by combining the DC(DEC205)-targeting E7 vaccine and PD-L1 blockade.
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Affiliation(s)
- Zhida Liu
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Department of Pathology, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - Hang Zhou
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Wenjun Wang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yang-Xin Fu
- Department of Pathology, University of Texas, Southwestern Medical Center , Dallas, TX, USA
| | - Mingzhao Zhu
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences , Beijing, China
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Mackay HJ, Wenzel L, Mileshkin L. Nonsurgical management of cervical cancer: locally advanced, recurrent, and metastatic disease, survivorship, and beyond. Am Soc Clin Oncol Educ Book 2016:e299-309. [PMID: 25993189 DOI: 10.14694/edbook_am.2015.35.e299] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Despite the declining incidence of cervical cancer as a result of the introduction of screening programs, globally it remains a leading cause of cancer-related death in women. Outcomes for patients who are diagnosed with anything but early-stage disease remain poor. Here we examine emerging strategies to improve the treatment of locally advanced disease. We discuss emerging biologic data, which are informing our investigation of new therapeutic interventions in persistent, recurrent, and metastatic cervical cancer. We recognize the importance of interventions to improve quality of life and to prevent long-term sequelae in women undergoing treatment. Finally, and perhaps most importantly, we recognize the need for global collaboration and advocacy to improve the outcome for all women at risk of and diagnosed with this disease.
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Affiliation(s)
- Helen J Mackay
- From the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre/Deptartment of Medicine, University of Toronto, Ontario, Canada; Department of Medicine and Public Health, University of California, Irvine, Irvine, CA; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Lari Wenzel
- From the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre/Deptartment of Medicine, University of Toronto, Ontario, Canada; Department of Medicine and Public Health, University of California, Irvine, Irvine, CA; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Linda Mileshkin
- From the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre/Deptartment of Medicine, University of Toronto, Ontario, Canada; Department of Medicine and Public Health, University of California, Irvine, Irvine, CA; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
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Koeneman MM, Kruitwagen RFPM, Nijman HW, Slangen BFM, Van Gorp T, Kruse AJ. Natural history of high-grade cervical intraepithelial neoplasia: a review of prognostic biomarkers. Expert Rev Mol Diagn 2015; 15:527-46. [PMID: 25703310 DOI: 10.1586/14737159.2015.1012068] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary.
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Affiliation(s)
- Margot M Koeneman
- GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
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Pathologic and imunohistochemical characterization of tumoral inflammatory cell infiltrate in invasive penile squamous cell carcinomas: Fox-P3 expression is an independent predictor of recurrence. Tumour Biol 2015; 36:2509-16. [PMID: 25557886 DOI: 10.1007/s13277-014-2864-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 11/17/2014] [Indexed: 10/24/2022] Open
Abstract
Penile carcinomas (PeCa) are relatively rare, but devastating neoplasms, more frequent among people of underprivileged socioeconomic status. There is mounting evidence that immune cells may trigger various mechanisms that enhance tumor growth and metastasis, but no data on the peritumoral inflammation is available for PeCa. The objectives of the present study are to evaluate the immunohistomorphology of tumoral inflammation in PeCa, and to correlate it with clinicopathological parameters, which could contribute to the prognostic evaluation. One hundred and twenty-two patients with the diagnosis of usual-type squamous cell penile carcinoma were included. Paraffin-embedded tissue was submitted to immunohistochemical evaluation of p16 protein, CD3, CD4, CD8, CD20, CD68, CD138, granzyme B, and Fox-P3. The Fisher's exact test was employed for comparison between histological variables and parameters, and the Kaplan-Meier method for the analysis of survival. Improved 5-year overall survival was significantly associated to age ≤60 years, stage I + II, tumor size T1 + T2, lymph node status N0, and absent perineural invasion. In a multivariate analysis age ≥60 years, presence of lymph node metastasis, urethral invasion, and high histologic grade retained a significantly more unfavorable outcome. Improved 5-year failure free survival was associated to stage of the disease I + II, lymph node status N0, absence of perineural, vascular, and urethral invasion, and Fox-P3 expression. In a multivariate analysis, presence of lymph node metastasis, perineural and vascular invasion, and of Fox-P3-positive lymphocytes together with low inflammatory infiltrate retained a significantly more unfavorable outcome. These results support the prognostic value of determining the levels of Fox-P3-positive lymphocytes by immunohistochemistry in PeCa, as this parameter adds value to the traditional clinicopathological features.
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32
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Rosales R, Rosales C. Immune therapy for human papillomaviruses-related cancers. World J Clin Oncol 2014; 5:1002-1019. [PMID: 25493236 PMCID: PMC4259927 DOI: 10.5306/wjco.v5.i5.1002] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 04/08/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Human papillomaviruses (HPVs) are a large family of double strand DNA viruses comprising more than 180 types. Infection with HPV is very common and it is associated with benign and malignant proliferation of skin and squamous mucosae. Many HPVs, considered low-risk such as HPV 6 and 11, produce warts; while high-risk viruses, such as HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58, induce tumors. About 5% of all cancers in men and women are associated with HPV infection. Because there are not antiviral drugs for HPV infection, current therapies for low-risk HPV infections involve physical removal of the lesion by cryotherapy, trichloracetic acid, laser, or surgical removal. Surgical procedures are effective in the treatment of pre-cancerous lesions, however after these procedures, many recurrences appear due to new re-infections, or to failure of the procedure to eliminate the HPV. In addition, HPV can inhibit recognition of malignant cells by the immune system, leading to the development of cancer lesions. When this occurs, radiotherapy and chemotherapy are then used. Unfortunately, about 50% of the HPV-cancer patients still die. In the past decade, a better knowledge of the natural history of the virus-host interaction and of the immune response against this viral infection has brought new therapeutic strategies geared to modulate the immune system to generate an efficient virus-specific cytotoxic response. Novel HPV protein-expressing vaccines have shown some significant clinical efficacy and systemic HPV-specific cytotoxic T cell responses. This review will describe the current status of the several therapeutic strategies used to treat HPV-induced lesions, and discuss the various new therapies now being tested.
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Strickler HD, Martinson J, Desai S, Xie X, Burk RD, Anastos K, Massad LS, Minkoff H, Xue X, D'Souza G, Levine AM, Colie C, Watts DH, Palefsky JM, Landay A. The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women. Viral Immunol 2014; 27:20-5. [PMID: 24494969 DOI: 10.1089/vim.2013.0097] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted.
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Affiliation(s)
- Howard D Strickler
- 1 Department of Epidemiology and Population Health, Albert Einstein College of Medicine , Bronx, New York
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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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Gómez-Lomelí P, Bravo-Cuellar A, Hernández-Flores G, Jave-Suárez LF, Aguilar-Lemarroy A, Lerma-Díaz JM, Domínguez-Rodríguez JR, Sánchez-Reyes K, Ortiz-Lazareno PC. Increase of IFN-γ and TNF-α production in CD107a + NK-92 cells co-cultured with cervical cancer cell lines pre-treated with the HO-1 inhibitor. Cancer Cell Int 2014; 14:100. [PMID: 25302050 PMCID: PMC4190300 DOI: 10.1186/s12935-014-0100-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 09/22/2014] [Indexed: 12/12/2022] Open
Abstract
Background Natural killer (NK) cells eliminate virus-infected and tumor cells through the release of perforins and granzymes; they also produce Interferon gamma (IFN-γ) and Tumor necrosis factor alpha (TNF-α), which induce apoptosis in target cells. Many tumors express Heme oxygenase 1 (HO-1), and this expression has been associated with avoiding immunosuppression and apoptosis. In this work, HO-1+ Cervical cancer cell (CCC) lines were pre-treated with HO-1 inhibitor and we assessed whether this inhibition enhanced the sensitivity of CCC to NK cell activity. Methods We assessed the expression of HO-1 in HeLa, SiHa, and C-33A CCC by Flow cytometry (FC). CCC were pre-treated with SnPP or ZnPP HO-1 inhibitors. After that, NK-92 cells were co-cultured with HeLa, SiHa, and C-33A CCC pre-treated or not with HO-1 inhibitors, and the expression of IFN-γ, TNF-α, CD107a, Granzyme B, NKp44, NKp46, NKp30, and NKG2D was evaluated by FC. Results CCC lines HeLa, SiHa, and C-33A expressed HO-1. Inhibition of HO-1 in these cells increased the expression of IFN-γ and TNF-α in CD107a + NK-92 cells. We observed a reduction in the expression of NKG2D, NKp46, and NKp30 in NK cells co-cultured with HeLa and SiHa cells, and when HeLa and SiHa cells were pre-treated with the HO-1 inhibitors, the expression of NKG2D and NKp30 in NK cells was restored. We observed a similar effect in NK cells co-cultured with C-33A cells in NKp30 expression. Conclusion Inhibition of HO-1 in CCC induces an increase in IFN-γ and TNF-α production in CD107a + NK-92 cells and restores NKG2D, NKp46 and NKp30 downmodulation in NK cells.
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Affiliation(s)
- Paulina Gómez-Lomelí
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico ; Programa de Doctorado en Ciencias Biomédicas Orientación Inmunología, Centro Universitario de Ciencias de la Salud (CUCS), UdeG, Guadalajara, Jalisco Mexico
| | - Alejandro Bravo-Cuellar
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico ; Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara (UdeG), Tepatitlán de Morelos, Jalisco Mexico
| | - Georgina Hernández-Flores
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico
| | - Luis Felipe Jave-Suárez
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico
| | - Adriana Aguilar-Lemarroy
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico
| | - José Manuel Lerma-Díaz
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico ; Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara (UdeG), Tepatitlán de Morelos, Jalisco Mexico
| | - Jorge Ramiro Domínguez-Rodríguez
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico ; Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingeniería, UdeG, Guadalajara, Jalisco Mexico
| | - Karina Sánchez-Reyes
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico ; Programa de Doctorado en Ciencias Biomédicas Orientación Inmunología, Centro Universitario de Ciencias de la Salud (CUCS), UdeG, Guadalajara, Jalisco Mexico
| | - Pablo Cesar Ortiz-Lazareno
- División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, Jalisco Mexico
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Dizon DS, Mackay HJ, Thomas GM, Werner TL, Kohn EC, Hess D, Rose PG, Covens AL. State of the science in cervical cancer: where we are today and where we need to go. Cancer 2014; 120:2282-8. [PMID: 24737608 DOI: 10.1002/cncr.28722] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/05/2014] [Accepted: 03/10/2014] [Indexed: 12/27/2022]
Abstract
Invasive cervical cancer remains an important global cause of death, despite the declining prevalence within the United States. Definitive therapies, including surgical resection of early-stage disease and chemoradiation for locally advanced disease, can be curative. For women who experience local or distant recurrences, the prognosis remains poor and better treatments are required. On July 18, 2013, The Gynecologic Oncology Group sponsored a State of the Science in Cervical Cancer Symposium with experts, researchers, clinicians, and interested stakeholders. This article summarize the progress that has been made, questions that require further investigation, and contemporary genomic findings and innovative treatments that may help inform the next generation of clinical trials for patients with cervical cancer.
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Affiliation(s)
- Don S Dizon
- Gillette Center for Gynecologic Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts
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37
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Shulzhenko N, Lyng H, Sanson GF, Morgun A. Ménage à trois: an evolutionary interplay between human papillomavirus, a tumor, and a woman. Trends Microbiol 2014; 22:345-53. [PMID: 24674660 DOI: 10.1016/j.tim.2014.02.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 02/21/2014] [Accepted: 02/21/2014] [Indexed: 01/02/2023]
Abstract
Cervical cancer is the third most common cancer in women with human papillomavirus (HPV) being a key etiologic factor of this devastating disease. In this article, we describe modern advances in the genomics and transcriptomics of cervical cancer that led to uncovering the key gene drivers. We also introduce, herein, a model of cervical carcinogenesis that explains how the interplay between virus, tumor, and woman results in the selection of clones that simultaneously harbor genomic amplifications for genes that drive cell cycle, antiviral response, and inhibit cell differentiation. The new model may help researchers understand the controversies in antiviral therapy and immunogenetics of this cancer and may provide a basis for future research directions in early diagnostics and personalization of therapy.
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Affiliation(s)
- Natalia Shulzhenko
- College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA
| | - Heidi Lyng
- Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Gerdine F Sanson
- Institute of Health Sciences, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, Corvallis, OR, USA.
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38
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Zhang LX, Liu ZN, Ye J, Sha M, Qian H, Bu XH, Luan ZY, Xu XL, Huang AH, Yuan DL, Wu YQ, Wang XX, Wang J, Huang JX, Ye LH. Artesunate exerts an anti-immunosuppressive effect on cervical cancer by inhibiting PGE2 production and Foxp3 expression. Cell Biol Int 2014; 38:639-46. [PMID: 24446394 DOI: 10.1002/cbin.10244] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 01/02/2014] [Indexed: 01/13/2023]
Abstract
Artesunate (ART), derived from a common traditional Chinese medicine, has beeen used an antimalarial for several years. In this study, the effect and mechanism of ART on anti-human cervical cancer cells was examined. The level of prostaglandin E2 (PGE2 ) and the population of CD4+CD25+Foxp3 regulatory T cells (Treg) in peripheral blood were detected by flow cytometry. In vivo antitumor activity was investigated in mice with cervical cancer by the subcutaneous injection of various concentrations of ART. The concentrations of PGE2 in the supernatants of CaSki cells were measured using an ELISA kit. Cyclooxygenase-2 (COX-2) and Foxp3 expression were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The effect of ART on the viability of CaSki and Hela cells was evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It was identified that the level of PGE2 and the population of CD4+CD25+Foxp3 Treg cells in the peripheral blood were significantly higher in cervical cancer patients and mice with cervical cancer. ART was capable of inhibiting orthotopic tumor growth, which correlated with a decrease in the level of PGE2 and the percentage of Treg cells in mice with cervical cancer. Furthermore, ART decreased COX-2 expression and the production of PGE2 in CaSki and Hela cells. Notably, the supernatants of CaSki cells treated with ART lowered the expression of Foxp3 in Jurkat T cells, which was capable of being reversed by exogenous PGE2 . Our data revealed that ART may elicit an anti-tumor effect against cervical cancer by inhibition of PGE2 production in CaSki and Hela cells, which resulted in the decrease of Foxp3 expression in T cells. Therefore, ART may be an effective drug for immunotherapy of cervical cancer.
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Affiliation(s)
- Li-Xin Zhang
- Department of Reproductive Medicine, Taizhou People's Hospital Affiliated of Nantong University of Medicine, Taizhou, 225300, China; Department of Gynecology, Taizhou People's Hospital Affiliated of Nantong University of Medicine, Taizhou, 225300, China
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39
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Long-peptide therapeutic vaccination against CRPV-induced papillomas in HLA-A2.1 transgenic rabbits. ACTA ACUST UNITED AC 2014; 3:134-142. [PMID: 25243025 DOI: 10.1016/j.trivac.2014.06.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Long peptide immunization is a promising strategy to clear established tumors. In the current study, we investigated the therapeutic effect of a naturally existing long peptide that contained two HLA-A2.1 restricted epitopes (CRPVE1/149-157 and CRPVE1/161-169) from cottontail rabbit papillomavirus (CRPV) E1 using our CRPV/HLA-A2.1 transgenic rabbit model. A universal Tetanus Toxin helper motif (TT helper) was tagged at either the N-terminus or the carboxyl-terminus of this long peptide and designated as TT-E1 peptide and E1 peptide-TT respectively. Four groups of HLA-A2.1 transgenic rabbits were infected with wild type CRPV DNA. Three weeks post-infection, the rabbits were immunized four times with TT-E1 peptide, E1peptide only, E1 peptide -TT or TT-control peptide with two-week intervals between immunizations. Tumor outgrowth was monitored and recorded weekly. After the third booster immunization, tumors on two of the four E1 peptide-TT immunized rabbits began to shrink. One animal from this group was free of tumors at the termination of the study. The mean papilloma size of E1 peptide-TT immunized rabbits was significantly smaller when compared with that of the three other groups (P<0.05, one way ANOVA analysis). It is interesting that E1 peptide-TT vaccination not only stimulated stronger T cell mediate immune responses but also stronger antibody generations. We conclude that the location of a TT helper motif tagged at the long peptide vaccine is critical for the outcome of therapeutic responses to persistent tumors in our HLA-A2.1 transgenic rabbit model.
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40
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Connolly K, Manders P, Earls P, Epstein RJ. Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control. Cancer Treat Rev 2013; 40:205-14. [PMID: 24051018 DOI: 10.1016/j.ctrv.2013.08.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 07/06/2013] [Accepted: 08/13/2013] [Indexed: 12/12/2022]
Abstract
The frequent occurrence of cutaneous squamous cell carcinomas (SCCs) containing weakly tumorigenic human papillomaviruses (HPVs) following iatrogenic immunosuppression for organ transplantation remains incompletely understood. Here we address this problem in the light of recent insights into (1) the association of low-risk β-HPVs with skin SCCs in the rare genetic syndromes of epidermodysplasia verruciformis and xeroderma pigmentosum, (2) the frequent recovery of post-transplant tumor control on substituting calcineurin-inhibitory with mTOR-inhibitory immunosuppression, (3) the unexpectedly favorable prognosis of node-positive SCCs containing high-risk α-HPVs originating in the activated immune niche of the oropharynx, (4) the rapid occurrence of HPV-negative SCCs in ultraviolet (UV)-damaged skin of melanoma patients receiving Raf-inhibitory drugs, and (5) the selective ability of β-HPV E6 oncoproteins to inhibit Notch tumor-suppressive signaling in cutaneous and mesenchymal tissues. The crosstalk so implied between oncogenic UV-induced mutations, defective host immunity, and β-HPV-dependent stromal-epithelial signaling suggests that immunosuppressants such as calcineurin inhibitors intensify mitogenic signalling in TP53-mutant keratinocytes while also abrogating immune-dependent Notch-mediated tumor repression. This emerging interplay between solar damage, viral homeostasis and immune control makes it timely to reappraise strategies for managing skin SCCs in transplant patients.
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Affiliation(s)
- Kate Connolly
- Department of Oncology, St. Vincent's Hospital, The Kinghorn Cancer Centre, UNSW Clinical School, Sydney, Australia
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41
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Xia M, Zhao MQ, Wu K, Lin XY, Liu Y, Qin YJ. Investigations on the clinical significance of FOXP3 protein expression in cervical oesophageal cancer and the number of FOXP3+ tumour-infiltrating lymphocytes. J Int Med Res 2013; 41:1002-8. [PMID: 23760912 DOI: 10.1177/0300060513488504] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES Investigations of FOXP3 protein expression in cervical oesophageal cancer cells and the number of FOXP3 + lymphocytes infiltrating tumour tissue were undertaken. METHODS FOXP3 protein expression and FOXP3 + tumour-infiltrating lymphocytes were studied immunohistochemically, in cervical oesophageal cancer tissue samples from 42 cases and paracancerous tissue samples from 30 of these cases. RESULTS The percentage of parenchymal cells expressing FOXP3 protein was significantly higher in cancer tissue (42.9%, 18/42) than in paracancerous tissue 6.67% (two of 30). FOXP3 + lymphocyte infiltration was significantly more frequent in cancer (38.1%, 16/42) than in paracancerous (13.33%, four of 30) tissue. FOXP3 protein expression in cancer parenchymal cells in patients with lymph node metastasis was significantly greater than expression in those without lymph node metastasis. FOXP3 protein expression was significantly higher in cancer tissue samples from clinical stage III or IV than those from stage I or II disease. FOXP3 + lymphocyte infiltration of tumours was significantly greater in patients with lymph node metastasis than in those without metastasis. CONCLUSIONS Abnormal FOXP3 expression in cervical oesophageal cancer parenchyma and FOXP3 + lymphocyte infiltration might be closely related to metastasis of this cancer by promoting immune escape of the tumour. FOXP3 might be a potential marker for the assessment of postoperative metastasis in cervical oesophageal cancer.
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Affiliation(s)
- Ming Xia
- Department of Otorhinolaryngology & Head and Neck Surgery, Qilu Hospital of Shandong University, Jinan, China.
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42
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Gao LJ, Gu PQ, Zhao W, Ding WY, Zhao XQ, Guo SY, Zhong TY. The role of globular heads of the C1q receptor in HPV 16 E2-induced human cervical squamous carcinoma cell apoptosis is associated with p38 MAPK/JNK activation. J Transl Med 2013; 11:118. [PMID: 23651874 PMCID: PMC3651870 DOI: 10.1186/1479-5876-11-118] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 04/29/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human papillomavirus type 16 (HPV 16) E2 protein is a multifunctional DNA-binding protein. HPV 16 E2 regulates many biological responses, including DNA replication, gene expression, and apoptosis. The purpose of this study was to investigate the relationship among the receptor for globular heads of the human C1q (gC1qR) gene expression, HPV 16 E2 transfection and apoptosis regulation in human cervical squamous carcinoma cells (C33a and SiHa). METHODS gC1qR expression was examined in C33a and SiHa cells using real-time PCR and Western blot analysis. Apoptosis of C33a and SiHa cells was assessed by flow cytometry. C33a and SiHa cell viability, migration and proliferation were detected using the water-soluble tetrazolium salt (WST-1) assay, a transwell assay and 3H-thymidine incorporation into DNA (3H-TdR), respectively. RESULTS C33a and SiHa cells that were transfected with a vector encoding HPV 16 E2 displayed significantly increased gC1qR gene expression and p38 mitogen-activated protein kinase (p38 MAPK)/c-jun N-terminal kinase (JNK) activation as well as up-regulation of cellular apoptosis, which was abrogated by the addition of gC1qR small interfering RNA (siRNA). Furthermore, the changes in C33a and SiHa cell viability, migration and proliferation that were observed upon HPV 16 E2 transfection were abrogated by SB203580 (a p38 MAPK inhibitor) or SP600125 (a JNK inhibitor) treatment. CONCLUSION These data support a mechanism whereby HPV 16 E2 induces apoptosis by silencing the gC1qR gene or inhibiting p38 MAPK/JNK signalling in cervical squamous cell carcinoma.
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Affiliation(s)
- Ling-juan Gao
- State Key Laboratory of Reproductive Medicine, Department of Clinical Laboratory, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Tianfei Alley, Nanjing Mochou Road, Nanjing, 210004, PR China.
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43
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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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44
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Mine KL, Shulzhenko N, Yambartsev A, Rochman M, Sanson GFO, Lando M, Varma S, Skinner J, Volfovsky N, Deng T, Brenna SMF, Carvalho CRN, Ribalta JCL, Bustin M, Matzinger P, Silva IDCG, Lyng H, Gerbase-DeLima M, Morgun A. Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer. Nat Commun 2013; 4:1806. [PMID: 23651994 PMCID: PMC4237593 DOI: 10.1038/ncomms2693] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 03/04/2013] [Indexed: 01/04/2023] Open
Abstract
Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus.
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Affiliation(s)
- Karina L. Mine
- Instituto de Imunogenética - Associação Fundo de Incentivo à Pesquisa (IGEN-AFIP), São Paulo SP, Brazil
- Universidade Federal de São Paulo, SP, Brazil
| | - Natalia Shulzhenko
- Instituto de Imunogenética - Associação Fundo de Incentivo à Pesquisa (IGEN-AFIP), São Paulo SP, Brazil
- Laboratory of Cellular and Molecular Immunology, NIAID, NIH, Bethesda, MD, United States
- College of Pharmacy, Oregon State University, Corvallis, OR, United States
| | - Anatoly Yambartsev
- Institute of Mathematics and Statistics, Department of Statistics, University of Sao Paulo, SP, Brazil
| | - Mark Rochman
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, NCI, NIH, Bethesda, MD, United States
| | - Gerdine F. O. Sanson
- Instituto de Imunogenética - Associação Fundo de Incentivo à Pesquisa (IGEN-AFIP), São Paulo SP, Brazil
| | - Malin Lando
- Department of Radiation Biology, Norwegian Radium Hospital, Oslo, Norway
| | - Sudhir Varma
- Bioinformatics and Computational Biosciences Branch, NIAID, NIH, Bethesda, MD, United States
| | - Jeff Skinner
- Bioinformatics and Computational Biosciences Branch, NIAID, NIH, Bethesda, MD, United States
| | - Natalia Volfovsky
- Advanced Biomedical Computing Center, SAIC-Frederick, Inc., Frederick, MD, United States
| | - Tao Deng
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, NCI, NIH, Bethesda, MD, United States
| | - Sylvia M. F. Brenna
- Medical School of Universidade Cidade de São Paulo (UNICID), Sao Paulo, Brazil
| | | | | | - Michael Bustin
- Protein Section, Laboratory of Metabolism, Center for Cancer Research, NCI, NIH, Bethesda, MD, United States
| | - Polly Matzinger
- Laboratory of Cellular and Molecular Immunology, NIAID, NIH, Bethesda, MD, United States
| | | | - Heidi Lyng
- Department of Radiation Biology, Norwegian Radium Hospital, Oslo, Norway
| | - Maria Gerbase-DeLima
- Instituto de Imunogenética - Associação Fundo de Incentivo à Pesquisa (IGEN-AFIP), São Paulo SP, Brazil
- Universidade Federal de São Paulo, SP, Brazil
| | - Andrey Morgun
- Instituto de Imunogenética - Associação Fundo de Incentivo à Pesquisa (IGEN-AFIP), São Paulo SP, Brazil
- Laboratory of Cellular and Molecular Immunology, NIAID, NIH, Bethesda, MD, United States
- College of Pharmacy, Oregon State University, Corvallis, OR, United States
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45
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Chen ZL, Gu PQ, Liu K, Su YJ, Gao LJ. The globular heads of the C1q receptor regulate apoptosis in human cervical squamous carcinoma cells via a p53-dependent pathway. J Transl Med 2012; 10:255. [PMID: 23268996 PMCID: PMC3567992 DOI: 10.1186/1479-5876-10-255] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2012] [Accepted: 12/21/2012] [Indexed: 01/09/2023] Open
Abstract
Background The globular heads of the human C1q receptor (gC1qR) localize predominantly to the mitochondrial matrix. gC1qR mediates many biological responses, including growth perturbation, morphological abnormalities and the initiation of apoptosis. The purpose of this study was to investigate the relationship between mitochondrial dysfunction, p53 status and gC1qR expression and the regulation of apoptosis in human cervical squamous carcinoma cells (C33a and SiHa). Methods Here, gC1qR expression was examined in human cervical tissues using real-time PCR and Western blot analysis. Apoptotic death of C33a and SiHa cells was assessed by flow cytometric analysis that detected the subG1 population. Mitochondrial function was assessed via ROS generation, the content of cytosolic Ca2+, and the change in mitochondrial membrane potential (Δψm). The viability and migration of C33a and SiHa cells were detected via the water-soluble tetrazolium salt (WST-1) assay and the transwell assay, respectively. Results gC1qR expression was decreased in cervical squamous cell carcinoma tissues compared with normal tissues. C33a and SiHa cells transfected with a vector encoding gC1qR displayed mitochondrial dysfunction and apoptosis, which was abrogated by the addition of a mutant form of p53 or p53 small interference RNA (siRNA). Furthermore, upon overexpression of gC1qR, cell viability and migration were significantly enhanced, and the apoptosis of C33a and SiHa cells were decreased when cells were treated with mutant p53 or p53 siRNA. Conclusions These data support a mechanism whereby gC1qR induces apoptosis through the mitochondrial and p53-dependent pathways in cervical squamous cell carcinoma.
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Affiliation(s)
- Zheng-Lin Chen
- Clinical Laboratory, Jiangsu Provicial Official Hospital, Nanjing 210024, China
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46
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Noh KH, Kim BW, Song KH, Cho H, Lee YH, Kim JH, Chung JY, Kim JH, Hewitt SM, Seong SY, Mao CP, Wu TC, Kim TW. Nanog signaling in cancer promotes stem-like phenotype and immune evasion. J Clin Invest 2012; 122:4077-4093. [PMID: 23093782 PMCID: PMC3484451 DOI: 10.1172/jci64057] [Citation(s) in RCA: 156] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 08/16/2012] [Indexed: 12/13/2022] Open
Abstract
Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.
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Affiliation(s)
- Kyung Hee Noh
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Bo Wook Kim
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Kwon-Ho Song
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Hanbyoul Cho
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Young-Ho Lee
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Jin Hee Kim
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Joon-Yong Chung
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Jae-Hoon Kim
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Stephen M. Hewitt
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Seung-Yong Seong
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Chih-Ping Mao
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - T.-C. Wu
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Tae Woo Kim
- Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pathology,
Department of Obstetrics and Gynecology,
Department of Oncology, and
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Piketty C, Selinger-Leneman H, Bouvier AM, Belot A, Mary-Krause M, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Grabar S. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. J Clin Oncol 2012; 30:4360-6. [PMID: 23091098 DOI: 10.1200/jco.2012.44.5486] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population. PATIENTS AND METHODS From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries. RESULTS In HIV-infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/μL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/μL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/μL. CONCLUSION Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM.
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48
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Liu Z, Su YJ, Gu PQ, Ji ZY, Wang XG, Gao LJ. The role of the globular heads of C1q receptor (gC1qR) gene in regulating apoptosis of human cervical squamous cell carcinoma. Cell Physiol Biochem 2012; 30:1181-90. [PMID: 23052251 DOI: 10.1159/000343308] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The globular heads of the human C1q receptor (gC1qR) are multi-compartmental and multi-functional cellular proteins. The list of biological responses mediated by the gC1qR includes growth perturbation and morphological abnormalities, along with the initiation of apoptosis. However, the effects of the gC1qR on the apoptosis of cervical squamous carcinoma cells (C33a and SiHa) have not been demonstrated. METHODS Here, human cervical tissues were examined for the expression of the gC1qR using real-time PCR and Western blot analysis. Apoptotic death of C33a and SiHa cells was assessed by flow cytometric analysis to detect the subG1 population. Viability, migration and proliferation of C33a and SiHa cells were detected via the water-soluble tetrazolium salt (WST-1) assay, the Transwell assay and the (3)H-thymidine incorporation into DNA assay ((3)H-TdR), respectively. RESULTS These data showed that expression of the gC1qR protein was significantly decreased in human cervical squamous cell carcinoma tissues relative to normal cervix tissues. C33a and SiHa cells transfected with a GFP-gC1qR vector resulted in the up-regulation of cellular apoptosis and an apparent increase in the expression of the p38 mitogen-activated protein kinase (p38 MAPK). Further, the changes in C33a and SiHa cells viability, migration and proliferation observed upon overexpression of gC1qR could be abrogated using the p38 MAPK inhibitor SB202190. CONCLUSION These data indicate that gC1qR inhibits viability, migration and proliferation of cervical squamous cells carcinoma via the p38 MAPK signalling pathway.
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Affiliation(s)
- Zhu Liu
- Clinical Laboratory, Huangdao District of Traditional Chinese Medicine, Qingdao, China
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49
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Siriaunkgul S, Utaipat U, Suwiwat S, Settakorn J, Sukpan K, Srisomboon J, Khunamornpong S. Prognostic Value of HPV18 DNA Viral Load in Patients with Early-Stage Neuroendocrine Carcinoma of the Uterine Cervix. Asian Pac J Cancer Prev 2012; 13:3281-5. [DOI: 10.7314/apjcp.2012.13.7.3281] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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50
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Bodelon C, Madeleine MM, Johnson LG, Du Q, Malkki M, Petersdorf EW, Schwartz SM. Genetic variation in CD83 and risks of cervical and vulvar cancers: a population-based case-control study. Gynecol Oncol 2012; 124:525-8. [PMID: 22134374 PMCID: PMC3727898 DOI: 10.1016/j.ygyno.2011.11.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 11/10/2011] [Accepted: 11/14/2011] [Indexed: 10/14/2022]
Abstract
OBJECTIVES The CD83 glycoprotein is a marker of dendritic cell maturation that may contribute to the T cell response to oncogenic human papillomavirus (HPV) infection. Whether single nucleotide polymorphisms (SNPs) in CD83 influence the risk of HPV-related genital cancers has not been adequately studied. We investigated whether the common genetic variation of the CD83 region was associated with the risks of cervical and vulvar cancers in a population-based case-control study conducted in the Seattle-Puget Sound Region. METHODS A total of 17 tagSNPs were genotyped in the CD83 region of 886 cervical cases, 517 vulvar cases and 1100 controls. Odds ratio (OR) and 95% confidence intervals (CI) were computed to assess the risk of cervical and vulvar cancers. The interaction between the tagSNPs and cigarette smoking was also explored. RESULTS TagSNPs in the CD83 chromosomal region were not associated with risk of either cervical or vulvar cancer. TagSNP rs853360 was associated with a decreased risk of cervical squamous cell carcinoma (SCC) (OR=0.80; 95% CI: 0.66-0.98). CONCLUSIONS Our results do not suggest that the common genetic variation of CD83 is related to cervical or vulvar cancers. The association between tagSNP rs853360 and risk of cervical SCC is likely to be due to chance. If larger or pooled studies confirm our results, CD83 has little or no influence in the risk of HPV-related cancers.
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Affiliation(s)
- Clara Bodelon
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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