Interleukin 10 promotes immune response by increasing the survival of activated CD8+ T cells in human papillomavirus 16-infected cervical cancer

ABSTRACT Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed ≥0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.

Download Full-text

Immune response to human papillomavirus 16 L1E7 chimeric virus-like particles: Induction of cytotoxic T cells and specific tumor protection

International Journal of Cancer ◽

10.1002/(sici)1097-0215(19990611)81:6<881::aid-ijc8>3.0.co;2-t ◽

1999 ◽

Vol 81 (6) ◽

pp. 881-888 ◽

Cited By ~ 90

Author(s):

Klaus Sch�fer ◽

Martin M�ller ◽

Stefan Faath ◽

Annette Henn ◽

Wolfram Osen ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Human Papillomavirus ◽

Cytotoxic T Cells ◽

Chimeric Virus ◽

Virus Like Particles ◽

Human Papillomavirus 16 ◽

Specific Tumor ◽

Tumor Protection

Download Full-text

A randomized phase II study of chemoradiation and pembrolizumab for locally advanced cervical cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps5601 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS5601-TPS5601 ◽

Cited By ~ 2

Author(s):

Linda R. Duska ◽

Timothy Norman Showalter ◽

Gina R. Petroni ◽

Timothy Bullock

Keyword(s):

Cervical Cancer ◽

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Cancer Patients ◽

Phase Ii ◽

Cd8 T Cells ◽

Cytotoxic T Cells ◽

Hpv Dna ◽

Randomized Phase Ii

TPS5601 Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360.

Download Full-text

Faculty Opinions recommendation of Human papillomavirus 16-associated cervical intraepithelial neoplasia in humans excludes CD8 T cells from dysplastic epithelium.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8767956.9291054 ◽

2011 ◽

Author(s):

Peter Stern

Keyword(s):

T Cells ◽

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Cd8 T Cells ◽

Intraepithelial Neoplasia ◽

Human Papillomavirus 16

Download Full-text

Human Papillomavirus 16-Associated Cervical Intraepithelial Neoplasia in Humans Excludes CD8 T Cells from Dysplastic Epithelium

The Journal of Immunology ◽

10.4049/jimmunol.1002756 ◽

2010 ◽

Vol 185 (11) ◽

pp. 7107-7114 ◽

Cited By ~ 82

Author(s):

Cornelia L. Trimble ◽

Rachael A. Clark ◽

Christopher Thoburn ◽

Nicole C. Hanson ◽

Jodie Tassello ◽

...

Keyword(s):

T Cells ◽

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Cd8 T Cells ◽

Intraepithelial Neoplasia ◽

Human Papillomavirus 16

Download Full-text

Human Papillomavirus Type 33 E7 Peptides Presented by HLA-DR*0402 to Tumor-Infiltrating T Cells in Cervical Cancer

Journal of Virology ◽

10.1128/jvi.74.14.6632-6636.2000 ◽

2000 ◽

Vol 74 (14) ◽

pp. 6632-6636 ◽

Cited By ~ 25

Author(s):

Hanni Höhn ◽

Henryk Pilch ◽

Susanne Günzel ◽

Claudia Neukirch ◽

Kirsten Freitag ◽

...

Keyword(s):

Cervical Cancer ◽

Immune Response ◽

T Cells ◽

Human Papillomavirus ◽

T Cell ◽

Tumor Infiltrating Lymphocytes ◽

Peripheral Blood Lymphocytes ◽

Tumor Rejection ◽

Autologous Tumor ◽

Hla Dr

ABSTRACT Several characteristics make human papillomavirus (HPV) amenable to vaccination. Anti-HPV-directed vaccines are based on the observation that HPV E6 and E7 oncoproteins are constitutively expressed in HPV-positive cervical cancer and may serve as tumor rejection antigens. Five HPV types (16, 18, 31, 33, and 45) account for 80% of cervical cancer. Until now, the type of immune response capable of mediating an effective antitumor response has not been defined. In order to define the anticancer-directed immune response in situ, we characterized CD4+ and CD8+ sorted T cells from peripheral blood lymphocytes, freshly harvested tumor tissue, and tumor-infiltrating lymphocytes (TIL) from a patient with cervical cancer. The HLA-DR-restricted CD4+ T-cell receptor VB16-, VA10-, VA21-, and VA22-positive CD4+ T-cell line derived from TIL recognizes autologous HLA-DR*0402+(HPV33+) cervical cancer cells, as determined by gamma interferon secretion. Testing of different peptides spanning the E7 gene revealed that the HPV3373–87 peptide ASDLRTIQQLLMGTV represents the immunodominant epitope which can also be presented by the DR*0401 allele to TIL. Such major histocompatibility complex class II-presented peptides represent attractive candidates to augment T-cell responses directed against autologous tumor cells.

Download Full-text

Human papillomavirus 16 is an independent predictor of better survival among patients with early cervical cancer

10.26226/morressier.5770e29bd462b80290b4ba75 ◽

2016 ◽

Author(s):

Maria Luiza Genta

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Independent Predictor ◽

Human Papillomavirus 16 ◽

Early Cervical Cancer

Download Full-text

Prediction of Prophylactic Peptide Vaccine Candidates for Human Papillomavirus (HPV): An Immunoinformatics and Reverse Vaccinology Approach

Current Proteomics ◽

10.2174/1570164617999200505095802 ◽

2020 ◽

Vol 17 ◽

Author(s):

Mehreen Ismail ◽

Zureesha Sajid ◽

Amjad Ali ◽

Xiaogang Wu ◽

Syed Aun Muhammad ◽

...

Keyword(s):

T Cells ◽

Human Papillomavirus ◽

T Cell ◽

Binding Affinity ◽

Cd8 T Cells ◽

Reverse Vaccinology ◽

Host Immune System ◽

T Cell Epitopes ◽

Multiple Alleles ◽

Vaccine Candidates

Background: Human Papillomavirus (HPV) is responsible for substantial morbidity and mortality worldwide. We predicted immunogenic promiscuous monovalent and polyvalent T-cell epitopes from the polyprotein of the Human Papillomavirus (HPV) using a range of bioinformatics tools and servers. Methods: We used immunoinformatics and reverse vaccinology-based approaches to design prophylactic peptides by antigenicity analysis, Tcell epitopes prediction, proteasomal and conservancy evaluation, host-pathogen protein interactions, and in silico binding affinity analysis. Results: We found two early proteins (E2 and E6) and two late proteins (L1 and L2) of HPV as potential vaccine candidates. Of these proteins (E2, E6, L1 & L2), 2-epitopes of each candidate protein for multiple alleles of MHC class I and II bearing significant binding affinity (>-6.0 kcal/mole). These potential epitopes for CD4+ and CD8+ T-cells were also linked to design polyvalent construct using GPGPG linkers. Cholera toxin B and mycobacterial heparin-binding hemagglutinin adjuvant with a molecular weight of 12.5 and 18.5 kDa were used for epitopes of CD4+ and CD8+ T-cells respectively. The molecular docking indicated the optimum binding affinity of HPV peptides with MHC molecules. This interaction showed that our predicted vaccine candidates are suitable to trigger the host immune system to prevent HPV infections. Conclusion: The predicted conserved T-cell epitopes would contribute to the imminent design of HPV vaccine candidates, which will be able to induce a broad range of immune-responses in a heterogeneous HLA population.

Download Full-text