Profiling HPV-16-specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients.
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ABSTRACT:
SUBMITTER: Bhatt KH
PROVIDER: S-EPMC7537390 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human cytomegalovirus (HCMV) can establish both nonproductive (latent) and productive (lytic) infections. Many of the proteins expressed during these phases of infection could be expected to be targets of the immune response; however, much of our understanding of the CD8(+)-T-cell response to HCMV is mainly based on the pp65 antigen. Very little is known about T-cell control over other antigens expressed during the different stages of virus infection; this imbalance in our understanding undermines the importance of these antigens in several aspects of HCMV disease pathogenesis. In the present study, an efficient and rapid strategy based on predictive bioinformatics and ex vivo functional T-cell assays was adopted to profile CD8(+)-T-cell responses to a large panel of HCMV antigens expressed during different phases of replication. These studies revealed that CD8(+)-T-cell responses to HCMV often contained multiple antigen-specific reactivities, which were not just constrained to the previously identified pp65 or IE-1 antigens. Unexpectedly, a number of viral proteins including structural, early/late antigens and HCMV-encoded immunomodulators (pp28, pp50, gH, gB, US2, US3, US6, and UL18) were also identified as potential targets for HCMV-specific CD8(+)-T-cell immunity. Based on this extensive analysis, numerous novel HCMV peptide epitopes and their HLA-restricting determinants recognized by these T cells have been defined. These observations contrast with previous findings that viral interference with the antigen-processing pathway during lytic infection would render immediate-early and early/late proteins less immunogenic. This work strongly suggests that successful HCMV-specific immune control in healthy virus carriers is dependent on a strong T-cell response towards a broad repertoire of antigens.
| S-EPMC153951 | biostudies-literature
Project description:High-risk human papillomavirus-associated cancers express viral oncoproteins (e.g., E6 and E7) that induce and maintain the malignant phenotype. The viral origin of these proteins makes them attractive targets for development of a therapeutic vaccine. Camelid-derived single-domain antibody fragments (nanobodies or VHHs) that recognize cell surface proteins on antigen-presenting cells (APC) can serve as targeted delivery vehicles for antigens attached to them. Such VHHs were shown to induce CD4+ and CD8+ T-cell responses against model antigens conjugated to them via sortase, but antitumor responses had not yet been investigated. Here, we tested the ability of an anti-CD11b VHH (VHHCD11b) to target APCs and serve as the basis for a therapeutic vaccine to induce CD8+ T-cell responses against HPV+ tumors. Mice immunized with VHHCD11b conjugated to an H-2Db-restricted immunodominant E7 epitope (E749-57) had more E7-specific CD8+ T cells compared with those immunized with E749-57 peptide alone. These CD8+ T cells acted prophylactically and conferred protection against a subsequent challenge with HPV E7-expressing tumor cells. In a therapeutic setting, VHHCD11b-E749-57 vaccination resulted in greater numbers of CD8+ tumor-infiltrating lymphocytes compared with mice receiving E749-57 peptide alone in HPV+ tumor-bearing mice, as measured by in vivo noninvasive VHH-based immune-positron emission tomography (immunoPET), which correlated with tumor regression and survival outcome. Together, these results demonstrate that VHHs can serve as a therapeutic cancer vaccine platform for HPV-induced cancers. Cancer Immunol Res; 6(7); 870-80. ©2018 AACR.
| S-EPMC6030498 | biostudies-literature
Project description:Antibodies against HPV16 early proteins have been shown to be promising biomarkers for the identification of HPV-driven oropharyngeal cancer (HPV-OPC) among OPC cases in multiple studies. A systematic literature search was performed to identify original research articles comparing HPV early antigen serology with established reference methods to determine molecular HPV tumor status. Random-effects models were used to calculate summary estimates for sensitivity and specificity of HPV16 E2, E6 and E7 serology for HPV-OPC. Subgroup analyses were performed to explore heterogeneity across studies and describe variables associated with test performance. We identified n = 23 studies meeting all eligibility criteria and included these in the meta-analysis. E6 serology showed the best performance with pooled sensitivity and specificity estimates of 83.1% (95% confidence interval (CI) 72.5-90.2%) and 94.6% (95% CI 89.0-97.4%), respectively, while E2 and E7 serological assays were highly specific (E2: 92.5% (95% CI 79.1-97.6%); E7: 88.5% (95% CI 77.9-94.4%)) but moderately sensitive (E2: 67.8% (95% CI 58.9-75.6%); E7: 67.0% (95% CI 63.2-70.6%)). Subgroup analyses revealed increased pooled sensitivity for bacterially (89.9% (95% CI 84.5-93.6%)) vs. in vitro expressed E6 antigen (55.3% (95% CI 41.0-68.7%)), while both showed high specificity (95.2% (95% CI 93.0-96.7%) and 91.1% (95% CI 46.6-99.2%), respectively). Pooled specificity estimates for HPV16 E2, E6 and E7 serology were significantly lower in studies utilizing HPV DNA PCR as the only molecular reference method compared to those using a combination of any two reference methods (HPV DNA, RNA, in situ hybridization (ISH), p16 immunohistochemistry (IHC)), or histopathological reference methods (ISH or p16 IHC) as stand-alone marker. In conclusion, HPV16 E6 seropositivity is a highly sensitive and specific biomarker for HPV-OPC. However, its performance differs between serological assays and depends on molecular reference methods.
| S-EPMC8234521 | biostudies-literature
Project description:Despite the fact that HPV-driven oropharyngeal cancer (HPV-OPC) has relatively low recurrence rates, intensive post-therapy monitoring remains the standard of care. Post-treatment biomarkers are needed to risk stratify HPV-OPC patients for more individualized surveillance intensity and which remain at higher recurrence risk.115 HPV-OPC patients (ascertained by p16 immunohistochemistry and/or in-situ hybridization) from a multicenter prospective case study (HOTSPOT) had blood collected at diagnosis, and 64 of these also had blood collected at post-treatment follow-up visits for up to two years. Samples were centrally tested for antibodies to the L1, E1, E2, E4, E6, and E7 proteins of HPV16.At diagnosis, most HPV-OPC cases were seropositive to HPV16 E6 (85%). In post therapeutic samples, HPV16 antibody level decreased slowly over time, but only 3 (of 51 cases seropositive at enrollment) dropped low enough to be classified as seronegative. At 3years after diagnosis, cumulative risk of recurrence was 10.2% and 0% in HPV16 E6 seropositive and E6 seronegative HPV-OPC cases, respectively (p=0.18). Risk of recurrence was increased, although not statistically significant, in those with higher HPV16 E6 antibody levels at diagnosis (per log antibody level, hazard ratio [HR]=1.81, 95%CI=0.47-6.92).This study confirms the high seroprevalence of HPV oncogenic antibodies at diagnosis of HPV-OPC. HPV16 E6 antibody levels decrease after treatment, but most cases remain seropositive for up to two years. HPV16 E6 antibody levels at diagnosis did not appear to be a strong predictor of recurrence.
| S-EPMC5788011 | biostudies-literature
Project description:Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
| S-EPMC8511029 | biostudies-literature
Project description:The fact that up to 30% of established high-grade squamous intraepithelial lesions (HSIL) of the cervix regress spontaneously presents the opportunity to identify clinically relevant human papillomavirus (HPV) viral epitopes associated with disease outcome. Two human HPV antigens, E6 and E7, are functionally required for initiation and maintenance of cervical cancer precursor lesions and invasive cervical cancer. The identification and characterization of endogenously processed HPV antigenic epitopes in closely characterized patient cohorts will provide insight into the reasons for success or failure of therapeutic approaches.We characterized the HPV-16 E6/E7-specific T-cell epitopes using E6/E7 overlapping peptide pools with peripheral blood lymphocytes obtained from normal healthy donors. We then analyzed the difference in the HPV-16 T-cell immune responses in HPV-16+ HSIL patients with or without spontaneous regression of lesions using the statistical methods.We have identified an HPV-16 E7-specific CD4+ T-cell epitope [amino acids (aa) 71-85] that was restricted by HLA-DQB1*0201. Analysis of peripheral blood lymphocytes obtained from 14 HLA-DQB1*02 patients with HPV-16+ HSILs showed that the HPV-16+ E7 peptide (aa 71-85)-specific CD4+ T-cell immune response was significantly higher in the group of patients with regression compared with the patients without regression (P value <0.05).The HPV-16 E7 peptide-specific CD4+ T-cell immune response correlates with spontaneous regression of established HPV16+ HSILs. Thus, this E7 epitope may be useful for the characterization of HPV-specific immune responses in patients infected with HPV-16 or immunized with HPV vaccines.
| S-EPMC3181117 | biostudies-literature
Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-negative and HPV-inactive OPCs from both African American and European American patients, and determine their biological and racial differences.
2014-03-05 | GSE55545 | GEO
Project description:Approximately 25% of all head and neck cancers (HNC), and up to 60% of oropharyngeal cancers (OPC) are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-active, -inactive and -negative OPC and determine their biological differences.
2014-03-05 | GSE55542 | GEO
Project description:Oropharyngeal carcinoma (OPC) can be classified into two equally prevalent subtypes depending on the presence of human papillomavirus (HPV). Patients with HPV-positive (HPV+) OPC represent a unique cohort with a distinct tumor biology and clinical behavior compared to HPV-negative (HPV-) OPC. Genetic studies have demonstrated chromosomal and gene expression changes associated with distinct subclasses of OPC; however, the proteomic consequences of HPV infection are not known. We analyzed sets of ten HPV+ and ten HPV- OPCs and ten normal adult oral epithelia using a standardized global proteomic analysis platform. This analysis yielded a total of 2,653 confidently identified proteins from which we chose 31 proteins on the basis of expression differences between HPV+, HPV- and normal epithelium for targeted protein quantitation. Analysis of differentially expressed proteins by HPV status revealed enrichment of proteins involved in epithelial cell development, keratinization and extracellular matrix organization in HPV- OPC, whereas enrichment of proteins in DNA initiation and replication and cell cycle control was found for HPV+ OPC. Enrichment analysis for transcription factor targets identified transcription factors E2F1 and E2F4 to be highly expressed in HPV+ OPC. We also found high expression of argininosuccinate synthase 1 in HPV+ OPC, suggesting that HPV+ OPC is more dependent on conditionally essential amino acid, arginine, and this was confirmed on a OPC-specific tissue microarray. These identified proteomic changes reveal novel driving molecular pathways for HPV+ and HPV- OPCs that may be pertinent in therapeutic strategies and outcomes of OPC.
| S-EPMC3479311 | biostudies-literature
Project description:BackgroundAccurate assessment of the prevalence of the human papilloma virus (HPV) in oropharyngeal tumours (OpSCC) is important because HPV-positive OpSCC are consistently associated with an improved overall survival. Recently, an algorithm has become available that reliably detects clinically relevant HPV in tumour tissue, however, no complete cohorts have been tested. The aim was to determine the prevalence of active high-risk HPV infection in a complete cohort of OpSCC collected over a 16-year period.MethodsUsing a triple algorithm of p16 immunohistochemistry, HPV-BRISH and HPV-PCR, we assessed the prevalence of active HPV infection in all OpSCC diagnosed in our hospital from 1997 to 2012 (n=193) and a random selection of 200 oral tumours (OSCC).ResultsForty-seven OpSCC (24%) were HPVGP PCR-positive; 42 cases were HPV16+, 1 HPV18+, 3 HPV33+ and 1 HPV35+. Brightfield in situ hybridisation did not identify additional HPV-positive cases. Human papilloma virus-associated tumour proportion increased from 13% (1997-2004) to 30% (2005-2012). Human papilloma virus-positivity was an independent predictor for longer disease-specific survival (HR=0.22; 95%CI:0.10-0.47). Only one OSCC was HPV+.ConclusionsIn our cohort, the incidence of HPV-associated OpSCC is low but increasing rapidly. The strict detection algorithm, analysis of disease-specific survival and the complete cohort, including palliatively treated patients, may influence the reported prevalence and prognostic value of HPV in OpSCC.
| S-EPMC4402463 | biostudies-literature