Potential value of in situ cellular immune response in HPV subtype 16 and 18 positive cervical cancer (original) (raw)
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Predictive value of cellular immune response in cervical cancer
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2009
Despite recent advances in the immune mechanisms of cervical cancer (CC), the relapse still remains an actual issue and recognition of new predictive biomarkers is essential. The purpose of this retrospective study was to investigate possible differences in the primary, in situ, cellular immune response between cervical carcinoma with and without relapse. Paraffin-embedded tissue samples from 61 consecutive women with CC (34 with and 27 without relapse) were immunostained for CD3, CD20 and CD45 cells. Immune cell profile densities were further assessed, assigning scores between 0 and 3: "0" meaning the absence of inflammatory infiltrate, "1+" low, "2+" intense and "3+" intense infiltrate with lymphoid follicles. Statistical analysis was performed in SPSS-13 software, p<0.05. Statistically significant intra- and peri-tumoral low numbers of several immune cell subtypes are strongly associated with relapse of disease within three and five year...
Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer
Cancer Microenvironment, 2012
Only a small proportion of women infected with Human Papillomavirus (HPV) develop cervical cancer. Host immune response seems to play a role eliminating the viral infection and preventing progression to cancer. Characterization of tumor infiltrating lymphocytes (TILs) in cervical pre-neoplastic lesions and cervical cancer may be helpful to understand the mechanisms that mediate this protection. The aim of this study was to determine if there are differences in the localization and density (cells/mm 2 ) of CD8+ T-cells, CD4+ T-cells and Tregs (CD25 + Foxp3+) in cervical pre-neoplastic lesions and cervical cancer. Immunohistochemical analysis of sections of 96 (26 CIN1, 21 CIN2, 25 CIN3, and 24 SCC) samples revealed that regardless of CIN grades, CD8+ T-cells are more abundant than CD4+, CD25+ and Foxp3+ cells in both the stroma and epithelium. There was a higher density of CD8+ cells in the stroma of cervical cancer compared to CIN3 (OR 0 4.20, 95% CI 1.2-15), CIN2 (OR 0 7.86, 95% CI 1.7-36.4) and CIN1 (OR 0 4.25, 95% CI 1.1-17). Studies evaluating whether these cells are recruited before or after cancer progression will be helpful to understand the role of these cells in the natural history of HPV-induced lesions.
Immunology, 2006
Human papillomaviruses (HPVs) are obligate epithelial pathogens and typically cause localized mucosal infections. We therefore hypothesized that T-cell responses to HPV antigens would be greater at sites of pathology than in the blood. Focusing on HPV-16 because of its association with cervical cancer, the magnitude of HPV-specific T-cell responses at the cervix was compared with those in the peripheral blood by intracellular cytokine staining following direct ex vivo stimulation with both virus-like particles assembled from the major capsid protein L1, and the major HPV oncoprotein, E7. We show that both CD4+ and CD8+ T cells from the cervix responded to the HPV-16 antigens and that interferon-γ (IFN-γ) production was HPV type-specific. Comparing HPV-specific T-cell IFN-γ responses at the cervix with those in the blood, we found that while CD4+ and CD8+ T-cell responses to L1 were significantly correlated between compartments (P = 0·02 and P = 0·05, respectively), IFN-γ responses in both T-cell subsets were significantly greater in magnitude at the cervix than in peripheral blood (P = 0·02 and P = 0·003, respectively). In contrast, both CD4+ and CD8+ T-cell IFN-γ responses to E7 were of similar magnitude in both compartments and CD8+ responses were significantly correlated between these distinct immunological compartments (P = 0·04). We therefore show that inflammatory T-cell responses against L1 (but not E7) demonstrate clear compartmental bias and the magnitude of these responses do reflect local viral replication but that correlation of HPV-specific responses between compartments indicates their linkage.
Infiltrating CD4 and CD8 lymphocytes in HPV infected uterine cervical milieu
Cancer Management and Research
Purpose: Tumor infiltrating lymphocytes (TILs) have been extensively described in antitumor immunity, but their functional alterations in the immunoediting processes during neoplastic progression in the uterine cervix are still not clear. Our aim was to gain insight into cervical tissue T cell populations, determine if there are any differences in the localization and quantity distribution of T lymphocytes, and to evaluate their role in disease regression or progression in the cervical neoplastic milieu. Patients and methods: Serial section analysis of immunohistochemically stained CD4 and CD8 lymphocytes was performed on a total number of 72 samples, categorized into four cohorts: 23 HPV non-infected (HPV-) normal cervix, 20 HPV infected (HPV+) normal cervix, 17 HPV+ low grade cervical intraepithelial neoplasia (CIN), and 12 HPV+ high grade CIN. Results: Low infiltrating lymphocytes (ILs) in normal cervix and high ILs in CIN were observed, while the trend of ILs increased with increasing grade of CIN, which was statistically significant (P<0.0001). Quantitative and localization analysis between the subsets of T cells showed that, in the epithelial layer, infiltrating CD8+ lymphocytes (CD8+ ILs) were significantly higher than CD4+ ILs in HPV+ normal cervix, while the trend decreased with increasing grade of CIN (P=0.011). Whereas, in the stromal layer, CD4+ ILs were predominant in all study groups and no statistical difference was found between these groups. However, tumor infiltrating CD8+ lymphocytes (CD8+ TILs) were noted to be significantly higher than CD4+ TILs in severe dysplastic cases. Conclusion: T cell infiltrates were predominant as the grade of the lesion progressed into more advanced lesions, which likely represent the lesions that have persisted over time. The variation in the infiltration rate and the location of CD4+ ILs and CD8 ILs may suggest the efficacious role of CD8 T cells in eliminating HPV infected cervical epithelial cells and also provides insight into the complex role of TILs in facilitating and mediating sustained antitumor responses, hence preventing tumor outgrowth.
Published by Wolters Kluwer - Medknow, 2025
The most common STD that triggers cervical cancer is the human papillomavirus. More than 20 types of human papillomavirus (HPV) can induce uterine cervical cancer. Almost all women acquire genital HPV infection soon after their first intercourse, with most of them clearing the virus within 3 years. An immune response is necessary to clear. The f irst responders to HPV infection are the innate immune system elements composed of macrophages, keratinocytes, natural killer cells, and natural killer T-lymphocytic (NKT) cells. Cytotoxic T lymphocytes (CTLs) comprise the second line of defense and kill HPV16-infected cells expressing various peptides derived from their transforming early viral oncoproteins, mainly E2•E6. Even though HPV can manage to trick away our immune systems, first of all, it is important to emphasize that HPV replication does not kill the host cells. It does not replicate viral antigens or cause inflammation. The HPV16 E6 and E7 genes suppress host cell type 1 interferons (IFNs), which are detectable after infection. The patient may have immunological tolerance; hence, there are no costimulatory signals from inflammatory cytokines like IFNs during antigen recognition. Evidence shows that HlA class I generations have been inhibited by HPV16 E5, which could protect this tumor cell from CTL attack. HPV16 E7 is responsible for initiating immunotolerance and increasing regulatory T cells (Treg) to repress immunological regression. Evasion from immune system protection plays a critical role in the outcome of persistent HPV infection and the development of cervical cancer. Vaccination against HPV16 and 18 during adolescence is the most effective method for preventing cervical cancer in women, considering the immunological processes involved. Keywords: Acquired immunity, Human papillomavirus, Immune escape, Natural immunity, Uterine cervical cancer
Cervical cancer cells express markers associated with immunosurveillance
2019
Cervical cancer is the second most frequent cancer in women in Mexico, and its development depends on the presence of human papillomaviruses in the uterine cervix. These oncogenic viruses transform cells where the control over cell cycle disappears, and the capacity to induce apoptosis is absent. On the other hand, some mutations confer to the transformed cells the ability to evade recognition by the immune system. The expression of markers of the immune system such as CD95, MICA/B, CD39, CD73, NKp30, NKp46, CD44, CD24, NKG2A, and CTLA-4 was analysed by flow cytometry on cervical cancer cells INBL (HPV 18, stage IVB), HeLa (HPV 18), CaSki (HPV 16), and C33A (HPV-). Our results showed the presence of atypical markers on cervical cancer cells; some of them are molecules involved in tumour cell recognition such as MICA/B and CD95. Other markers associated with immune system escape, such as CD39, CD73, and CTLA-4, were also present. Furthermore, we found that some cervical cancer cells expressed typical markers of NK cells like NKp30, NKp46, NKG2A, and KIR3DL1. It is not clear whether these molecules confer any gain to the tumour cells or if they represent a disadvantage, but we hypothesise that these molecules that are present in cervical cancer cells allow them to mimic in front of the immune system.
Immune response in cervical intraepithelial neoplasms
European Journal of Gynaecological Oncology, 2021
The current study aims perform a comprehensive overview of the topic immune response in cervical intraepithelial neoplasms, summarizing the findings of literature. Data sources: PubMed database. Methods of study selection: A search for the following descriptors was performed in the PubMed database: descriptor ''immune response in cervical cancer and Human Papilloma Virus (HPV)''; ''immunotherapy in premalignant cervical lesions''. Tabulation, integration and results: The articles identified were published between 1967 and 2021. We selected 85 articles for review on the subject (reference 16 onwards). This literature review shows the important role that the immune system plays in the development and progression of cervical cancer. Immune response in pre-neoplastic cervical lesions includes host defense mechanisms against the HPV, adaptive immunity and the function of cytokines. Predictive factors of viral persistence and progression of premalignant lesions may also be associated with immune response. Conclusion: One of the determining factors for the persistence or elimination of HPV infections and their evolution to pre-neoplastic lesions is the cellular immune response, as the progression or regression of the tumor depends on the type and amount of cytokines secreted by the body. The investigation of these immune reactions may provide new therapeutic targets for cervical intraepithelial neoplasms.
Cellular immunity against human papillomavirus associated cervical cancer
Seminars in Virology, 1996
Human papillomaviruses contain a double stranded circular DNA genome of about 8 kilobases in size. More than 95 genotypes have been described of which several types are associated with cancer, like cervical carcinoma. The HPV types associated with cervical carcinoma (high risk types) are predominantly HPV16 and 18 and less frequently HPV31, 33, 35 and 45. 3, HPV DNA is detected in nearly 100% of cervical carcinomas and 60% of these are accounted for by HPV16. 4, Development of cervical cancer is preceded by cervical dysplasia, classified as cervical intraepithelial neoplasia (CIN) grade I-III based on histological criteria. The prevalence of HPV increases from about 60% in CIN I to almost 100% in CIN III. In cervical smears of symptom-free women, the prevalence of HPV is dependent on age and varies from 15 to 20% (15-30 years of age) and from 5 to 10% (over 30 years of age). 4,9 The high risk HPV are transmitted via sexual intercourse 10,11 after which they infect the basal layers of the epithelium of the anogenital tract in which they replicate. 12,13 Since these replication conditions cannot yet be mimicked in vitro, immunologic research on HPV has been hampered by the lack of obtaining sufficient amounts of intact HPV16 virions. The early region 6 and 7 (E6 and E7)-encoded oncoproteins of the high risk HPV genotypes were shown to bind the tumor suppressor gene products p53 and pRb, respectively. As a result the cell cycle control mechanisms in which p53 and pRb play a key role are deregulated. 14,15 These findings indicate a direct involvement of the E6 and E7 proteins in oncogenesis. Since E6 and E7 are the only HPV proteins constitutively expressed in cervical cancer cells 16,17 and maintenance of the transformed phenotype of cells transfected with HPV16 depends on intact E6 and E7 expression, 19,20 the E6 and E7 oncoproteins seem suitable targets for T-cell mediated immunotherapy of cervical cancer.
Gynecologic Oncology, 2005
Objectives. The specific CTL response against human papillomavirus (HPV) antigens in women with cervical cancer has been poorly studied. Immunological monitoring of this response is central for understanding the principles that underlie successful immunotherapeutic strategies. The aim of the study was to investigate the HPV16 E6/E7-specific CTL immune response in a group of untreated HPV16-positive cervical cancer patients.
Cancer Research, 2007
In a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16 + )-induced or HPV18 + -induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4 + , CD8 + , and regulatory T cells as well as by calculation of the ratio of CD8 + /CD4 + T cells and CD8 + / regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6-and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN À ) or presence (LN + ) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8 + T-cell tumor infiltration, a higher CD8 + /CD4 + T-cell ratio, and higher CD8 + /regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR + ) or absence (IR À ) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8 + T cells was found in the group of LN À patients displaying a concomitant systemic tumor-specific immune response (LN À IR + ). CD8 + T-cell infiltration in LN À IR À patients was comparable with that of LN + patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN À patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis. [Cancer Res 2007;67(1):354-61] Note: S.J. Piersma, E.S. Jordanova, and M.I.E. van Poelgeest contributed equally to this work.