The detection of circulating human papillomavirus-specific T cells is associated with improved survival of patients with deeply infiltrating tumors (original) (raw)
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International Journal of Cancer, 2007
Human papillomavirus (HPV) is a necessary factor in the pathogenesis of cervical cancer. Circulating HPV-specific T-cells responding to the E6 and E7 HPV proteins can be detected only in half of cervical cancer patients. Potential explanations for the absence of this response are lack of sufficient amounts of antigen to activate the immune response or local immune escape mechanisms. We studied the relationship between HPV 16 E6/E7 oncogene mRNA expression, human leukocyte antigen (HLA) expression on tumor cells and the presence of circulating E6-and E7-specific T-cell responses in cervical cancer patients. The amount of antigen was assessed by HPV E6/E7 mRNA expression levels measured by quantitative polymerase chain reaction. HLA Class I and Class II expression on tumor cells was analyzed by immunohistochemistry. A proliferative HPV-specific T-cell response was detected in 15/29 patients. The amount of HPV E6/E7 mRNA was not related to the presence of immune response. HLA Class I expression was downregulated in 19 patients and completely lost in 7 patients. HLA Class II expression was upregulated in 18 patients. HLA Class I expression on tumor cells showed a strong correlation with immunity (p 5 0.001). Explicitly, all patients with complete HLA loss lacked HPV specific T-cell responses. The presence of circulating HPV-specific T-cells might reflect ongoing antitumor response that is sustained by CD81 T-cells killing HLA Class I positive cancer cells. We hypothesize that HLA Class I expression status on tumor cells might as well influence the response to HPV E6/E7 directed immunotherapy. ' 2007 Wiley-Liss, Inc.
Microbial Biosystems
Human papilloma virus (HPV) related cervical cancer (CC) remains a significant cause of mortality, especially in developing nations. Practical, cheap, and responsive biomarkers are required to diagnose and prevent large-scale CCs and other cancers associated with HPV. This research aimed to investigate HPV-Human leukocyte Antigen-G (HLA-G) interaction with the cervical cancer immune modulation: Hypothesizing HPV-specific HLA markers might be accurate and costeffective preventive biomarkers. In addition to assessing the host immune response by immunophenotyping of CD57 natural killer T-cells. Forty-five DNA and serum samples of the patients were divided into two groups; twenty-three cases with HPV infection associated with cervical cancer and twenty-two controls with HPV infection without cervical cancer. Real-Time Quantitative polymerase chain reaction (RT-PCR) was used for HLA-G messenger RNA expression. Immunophenotyping by flow cytometry was carried out using specific monoclonal antibodies against CD57 expressed on CD8+ T-cells. The results indicated that 69.6% of the cases showed HLA-G expression compared to only 22.7% of the controls, and the difference was statistically significant at p<0.01. Cases have eight times the risk of expression among controls since odd ratio (OR) =7.8. Also, 65.2% of the cases showed CD57 + expression compared to 36.4% of the controls, and the difference was marginally significantly different at p= 0.053. Cases have nearly three times the risk of expression among controls since OR=3.3. Although the lower limit of the 95% confidence interval is <1, indicating that in the population, this increase in risk may not be present. HPV-specific HLA-G marker test might be an accurate and cost-effective preventive biomarker with potential application for cervical cancer.
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2014
There is no doubt that the association between infection of the cervical epithelium by carcinogenic Human Papilloma Virus (HPV), particularly types 16 and 18, and cervical cancer (CC) is responsible for the activation of the immune response (IR). Research on tumor infiltrating lymphocytes at the primary tumor site could give us important information on how the immune cells are fighting against cancer. The aims of our study were to assess HPV status and to evaluate the significance of in situ cellular IR in CC. We performed a two-step retrospective analysis of IR in 18 CC: evaluation of HPV 16 and 18 infections by in situ hybridization and immune biomarkers (CD20, CD3, CD45) by immunohistochemistry. Immune cell profile, densities (assigned scores "0" if no inflammatory infiltrate, "1+" low, "2+" intense), tissue distribution and classical negative prognosis factors in relationship with survival and relapse were further assessed. We successfully demonstra...
International Journal of Cancer, 2008
Human papillomavirus (HPV)-induced malignancies are frequently infiltrated by lymphocytes. To comprehend the contribution of HPV-specific T cells in this anti-tumor response we developed a method that allowed the analysis of the presence and specificity of cervix-infiltrating and draining lymph node resident T cells in a group of 74 patients with cervical malignancies, 54 of which were induced by HPV16 or HPV18. We detected the presence of HPV16 or HPV18-specific T cells in at least 23 of the 54 HPV-16 or -18 positive patients, and not in the 20 controls. Detailed studies resulted in the identification of 17 novel CD41 and CD81 T cell epitopes and their HLA-restriction elements, and also revealed that the HPV-specific immune response was aimed at both E6 and E7 and showed no preferential recognition of immunodominant regions. Unexpectedly, the vast majority of the CD41 T cell epitopes were presented in the context of the less abundantly expressed HLA-DQ and HLA-DP molecules. Since the identified T cell epitopes constitute physiological targets in the immune response to HPV16 and HPV18 positive tumors they will be valuable for detailed studies on the interactions between the tumor and the immune system. This is crucial for the optimization of cancer immunotherapy in patients with pre-existing tumor-immunity. ' 2007 Wiley-Liss, Inc.
Markers of HPV infection and survival in patients with head and neck tumors
International Journal of Cancer, 2013
The purpose of this study was to determine whether changes in human papillomavirus (HPV) DNA prevalence in oral rinses and/or HPV-specific antibody levels in the sera of patients with oral/oropharyngeal cancer have prognostic significance. One hundred and forty-two patients with oral/oropharyngeal tumors were enrolled. The presence of HPV DNA was assayed in tumor tissue and oral rinses and HPV-specific antibodies were assessed in the sera. Oral rinses were collected before treatment and one year after the treatment. Sera were drawn before treatment, one month, and one year after the end of the treatment. Altogether, 59.2% of tumors were HPV positive. The presence of HPV DNA in the tumors correlated with HPV DNA positivity in oral rinses and with HPV-specific antibodies in the sera. Out of 66 patients with HPV-positive oral rinses at enrolment, 84.8% became negative at one-year follow-up, while most patients remained seropositive for HPV-specific antigens. However, the mean titers of HPV16 E6 and/or E7 antibodies at follow-up were significantly lower. Of 16 patients with recurrences at followup (alive on second sampling), six were positive at enrolment for HPV16 E6 and/or E7 antibodies. In five of these, no decrease in antibody levels was observed. Titers of antibodies specific for HPV16 capsid antigens did not change during the follow-up. Our data suggest that the detection of antibodies specific for the HPV 16 E6 and E7 oncoproteins may serve not only as a marker of HPV etiology, but also as a marker of recurrence and a prognostic indicator in patients with HPV-positive tumors.
International Journal of Cancer, 2006
It has been suggested that local invasive procedures may alter the natural course of (pre)malignant cervical disease. This could be due to partial excision of the lesions, or via induction of cellular immunity against human papillomavirus (HPV) by the local invasive procedures. We studied the influence of local invasive procedures on HPV-16 E7 specific immune responses in patients with different grades of cervical intra-epithelial neoplasia (CIN) and different stages of cervical cancer. Blood was obtained at intake and after invasive procedures from patients with CIN or cervical cancer. Antigen specific T-cell responses were measured by IFN-c ELISPOT analysis, after stimulation with recombinant HPV-16 E7 protein. As expected, HPV-16 E7 specific IFN-c T cell responses were more frequent in HPV-16 DNA positive patients compared with that in HPV-16 DNA negative patients (39/50 vs. 16/36, (p 5 0.006, v 2 test). After invasive procedures, a small number of HPV-16 DNA positive CIN patients, but a considerable proportion of HPV-16 DNA positive cervical cancer patients, showed an enhancement of T cell responses against HPV-16 E7. Induction of T cell reactivity was most pronounced in cervical cancer patients who had undergone previous invasive procedures. Both CD4 1 and CD8 1 T cells showed E7 specific IFN-c production upon in-vitro stimulation. Our study shows that invasive procedures may enhance HPV-specific cell-mediated immunity in a considerable number of patients with cervical cancer, but in only a minority of CIN patients. Our data indicate that invasive procedures should be considered as possible confounding factors when analyzing the effectiveness of therapeutic immunization studies, especially, when induction of HPV-specific immune responses is used as intermediate end-point. ' 2005 Wiley-Liss, Inc.