Kobayashi A, Weinberg V, Darragh T et al.Evolving immunosuppressive microenvironment during human cervical carcinogenesis. Mucosal Immunol 1:412-420

Department of Obstetrics, Gynecology, Reproductive Science, University of California at San Francisco, San Francisco, California, USA.
Mucosal Immunology (Impact Factor: 7.37). 10/2008; 1(5):412-20. DOI: 10.1038/mi.2008.33
Source: PubMed


Chronic infection with human papillomavirus (HPV) can result in cervical cancer. To understand how HPV escapes immune eradication, we examined biophenotypes of immune cells in human normal cervix, cervical intraepithelial neoplasia (CIN), and cancer. Expression and cellular localization of Forkhead box protein-3 (FOXP3), indolamine 2,3-dioxygenase (IDO), interleukin (IL)-10, and interferon (IFN)-gamma were examined by immunofluorescence and immunohistochemistry. Mean cell densities of stromal FOXP3+ cells, IDO+ cells, IL-10+ cells, CD1a+ cells, and macrophages significantly increased from normal cervix to cancer, whereas densities of IFN-gamma+ and MMP-9+ cells increased from normal cervix to CIN but decreased in cancer. Flow cytometry confirmed significant elevation of cervical T cells expressing IFN-gamma and transforming growth factor-beta in CIN compared with normal cervix. Upon activation, a significantly increased proportion of cervical T cells expressed IFN-gamma in CIN than normal. A unique subset of morphologically immature stromal dendritic cells expressing IL-10 and IDO was more numerous in cancer than in normal cervix and CIN. The potentially suppressive immune milieu in the cervix may be permissive of HPV-associated cervical carcinogenesis.

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Available from: Karen Smith-McCune, Aug 21, 2014
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    • "Immunotherapy against the tumor is often inefficient because of the existence of a local immunosuppressive tumor milieu with impaired tumor cell antigen presentation and resistance of tumor cells against effector mechanisms of T-cells. The immunosuppressive milieu might be created during the stage of cervical intraepithelial neoplasia (CIN), since numbers of IDO, IFNγ, IL10, and FoxP3 expressing cells are elevated in CIN compared to normal cervical tissue (66). When HPV16 E7, an envelope- and oncoprotein of HPV was expressed under the keratin-14 promoter (K14E7) in a skin grafting model, graft rejection was prevented suggesting that HPV16E7 induced an immunotolerogenic environment (67). "
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    ABSTRACT: Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.
    Full-text · Article · Aug 2014 · Frontiers in Immunology
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    • "In this report, we shed light on the immunomodulatory effects of HPV16 E2 as a repressor of MDSCs and MDSC-related mediators. It has been shown that IDO expression levels are higher in cervical cancer than in normal cervix, in CIN, [31] and in HPV16 E7-transduced skin [32]. The inhibition of IDO reversed local immune suppression and inhibited tumor growth by promoting NK cell accumulation and cytotoxicity [32] [33]. "
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    ABSTRACT: The balance between active immune responses against human papillomavirus (HPV) and HPV-induced immune escape regulates viral clearance and carcinogenesis. To understand the role of the early viral protein HPV16 E2 in host innate immune responses, the HPV16 E2-transfected murine squamous cell carcinoma cell line SCCVII (SCC/E2) was generated and anti-tumor responses in T-cell-depleted mice were evaluated. Tumor growth of SCC/E2 was markedly reduced. Cytotoxicity against the NK-sensitive targets YAC-1 and SCCVII was clearly enhanced in SCC/E2-inoculated mice. Despite the comparable ratio of NK cells, the proportion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) was significantly decreased in SCC/E2-inoculated mice. The transcription of MDSC-related mediators such as inducible nitric oxide synthase, indoleamine 2,3-dioxygenase, and heme oxygenase-1 was significantly impaired in the SCC/E2-inoculated tumor tissues on day 3. Our results suggest that HPV16 E2 promotes anti-tumor innate effector function by modulating immunoregulatory events mediated by MDSCs and their mediators. This report describes a new role for HPV16 E2 as a local immunomodulator at infected sites.
    Full-text · Article · Apr 2014 · Biochemical and Biophysical Research Communications
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    • "It is safe to note that reduced Th1 response and increased Th2 response lead to suppression of cellular immunity and lesion progression [56, 57]. IL2 and TNF-α  levels (both belong to the Th1 pattern) appear lower in HPV lesion than in healthy women [57, 58]. Although IL4 levels, characteristic Th2 product, seem to increase in LSIL, as the lesion progresses they decrease slightly. "
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    ABSTRACT: High prevalence and mortality rates of cervical cancer create an imperative need to clarify the uniqueness of HPV (Human Papillomavirus) infection, which serves as the key causative factor in cervical malignancies. Understanding the immunological details and the microenvironment of the infection can be a useful tool for the development of novel therapeutic interventions. Chronic infection and progression to carcinogenesis are sustained by immortalization potential of HPV, evasion techniques, and alterations in the microenvironment of the lesion. Inside the lesion, Toll-like receptors expression becomes irregular; Langerhans cells fail to present the antigens efficiently, tumor-associated macrophages aggregate resulting in an unsuccessful immune response by the host. HPV products also downregulate the expression of microenvironment components which are necessary for natural-killer cells response and antigen presentation to cytotoxic cells. Additionally HPV promotes T-helper cell 2 (Th2) and T-regulatory cell phenotypes and reduces Th1 phenotype, leading to suppression of cellular immunity and lesion progression to cancer. Humoral response after natural infection is inefficient, and neutralizing antibodies are not adequate in many women. Utilizing this knowledge, new endeavors, such as therapeutic vaccination, aim to stimulate cellular immune response against the virus and alter the milieu of the lesion.
    Full-text · Article · Aug 2013 · Infectious Diseases in Obstetrics and Gynecology
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