Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

Oerke, Sebastian; Höhn, Hanni; Zehbe, Ingeborg; Pilch, Henryk; Schicketanz, K. H.; Hitzler, W; Neukirch, Claudia; Freitag, Kirsten; Maeurer, Markus

doi:10.1002/ijc.20794

Cited by 24 publications

(22 citation statements)

References 47 publications

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“…6). We also identified another example of the HLA class I binding promiscuity in the HPV 16 E7 protein among previously published works (19,26,31) (Fig. 6).…”

Section: Vol 81 2007 T-cell Epitopes Of the Hpv 16 E6 Protein 1413supporting

confidence: 66%

HLA Class I Binding Promiscuity of the CD8 T-Cell Epitopes of Human Papillomavirus Type 16 E6 Protein

Nakagawa

Kim²,

Gillam³

et al. 2007

J Virol

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One of the critical steps in the progression to cervical cancer appears to be the establishment of persistent human papillomavirus (HPV) infection. We have demonstrated that the lack of cytotoxic T-lymphocyte response to HPV type 16 (HPV 16) E6 protein was associated with persistence and that the potential presence of dominant CD8 T-cell epitopes was most frequently found (n ‫؍‬ 4 of 23) in the E6 16-40 region by examining the pattern of CD8 T-cell epitopes within the E6 protein in women who had cleared their HPV 16 infections. The goal of this study was to define the minimal/optimal amino acid sequences and the HLA restricting molecules of these dominant CD8 T-cell epitopes as well as those of subdominant ones if present. Three dominant epitopes, E6 29-38 (TIHDIILECV; restricted by the HLA-A0201 molecule), E6 29-37 (TIHDIILEC; restricted by B48), and E6 31-38 (HDIILECV; restricted by B4002), and one subdominant epitope, E6 52-61 (FAFRDLCIVY; restricted by B35) were characterized. Taken together with a previously described dominant epitope, E6 52-61 (FAFRDLCIVY; restricted by B57), the CD8 T-cell epitopes demonstrated striking HLA class I binding promiscuity. All of these epitopes were endogenously processed, but the presence of only two of the five epitopes could have been predicted based on the known binding motifs. The HLA class I promiscuity which has been described for human immunodeficiency virus may be more common than previously recognized.Cervical cancer is the second most common cancer among women worldwide (CANCERMondial [http://www-dep.iarc .fr/], 2005). The association between human papillomavirus (HPV) infections, most commonly HPV type 16 (HPV 16), and the development of cervical cancer has been well described (46). However, the exact mechanisms leading from HPV infection to malignancy are not well understood. One of the critical steps in the progression to cervical cancer appears to be the establishment of persistent infection. Epidemiologic evidence suggests that over 90% of women are able to clear their HPV infections, including the oncogenic HPV 16 type. The remaining women whose HPV infections persist are at risk for the development of invasive cancer. The E6 and E7 proteins of high-risk HPV types are expressed early after infection and are known to mediate cell transformation by interacting with products of cellular human tumor suppressor genes. The E6 protein can bind and promote degradation of cell-encoded p53, while the E7 protein interacts with the retinoblastoma susceptibility gene product (7,18,32,36,37,41). In a longitudinal study using multiple chromium release assays, we found that detectable responses to HPV 16 E6 were more common in those women who cleared their HPV 16 infections than in women who had viral persistence. Interestingly, no association was found for E7 (29). Furthermore, we examined the pattern of HPV 16 E6 CD8 T-cell epitopes recognized by women who had evidence of HPV 16 clearance (27). Among 23 women with evidence of HPV 16 clearance, we found evidence of potentia...

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“…6). We also identified another example of the HLA class I binding promiscuity in the HPV 16 E7 protein among previously published works (19,26,31) (Fig. 6).…”

Section: Vol 81 2007 T-cell Epitopes Of the Hpv 16 E6 Protein 1413supporting

confidence: 66%

HLA Class I Binding Promiscuity of the CD8 T-Cell Epitopes of Human Papillomavirus Type 16 E6 Protein

Nakagawa

Kim²,

Gillam³

et al. 2007

J Virol

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“…Due to efforts by many investigators [2,4,6,7,11,14,18,22,32], numerous CD8 T-cell epitopes of HPV 16 E6 and E7 proteins have been described, and CD8 epitopes relevant to the vast majority of the population are known. On the other hand, only a handful of HPV-specific CD4 T-cell epitopes have been described [i.e., E7 50-62 (33 amino acids long) restricted by DR15, E7 43-77 (35 amino acids long) restricted by DR3, and E7 35-50 (16 amino acids long) restricted by DQ2 described by van der Burg et al [30]; and E7 61-80 (20 amino acids long) restricted by DR9 described by Okubo et al [19].…”

Section: Discussionmentioning

confidence: 99%

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

Wang

Santin

Bellone

et al. 2008

Cancer Immunol Immunother

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Previously, safety and immunogenicity of human papillomavirus type 16 (HPV16) or 18 E7-pulsed dendritic cells (DC) vaccinations were demonstrated in a dose-escalation Phase I clinical trial which enrolled ten patients diagnosed with stage IB or IIA cervical cancer (nine HPV 16-positive, one HPV 18-positive). The goal of the study was to define the T-cell epitopes of HPV 16 or 18 E7 protein in these patients in order to develop new strategies for treating HPV-associated malignancies. This was accomplished through establishing T-cell lines by stimulating peripheral blood mononuclear cells with autologous mature DC pulsed with the HPV 16 or 18 E7 protein, examining the T-cell responses using ELISPOT assays, and isolating E7-specific T-cell clones based on IFN-γ secretion. Then, the epitope was characterized in terms of its core sequence and the restriction element. Twelve T-cell lines from eight subjects (seven HPV 16-positive, one HPV 18-positive) were evaluated. Positive Tcell responses were demonstrated in four subjects (all HPV 16-positive). All four were positive for the HPV 16 E7 46-70 (EPDRAHYNIVTFCCKCDSTLRLCVQ) region. T-cell clones specific for the E7 47-70 region were isolated from one of the subjects. Further analyses revealed a novel, naturally processed, CD4 T-cell epitope, E7 58-68 (CCKCDSTLRLC), restricted by the HLA-DR17 molecule.

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“…Given their key role in cancerous transformation, a large body of research focusing on E6 and E7 as therapeutic vaccine targets has been conducted. Multiple MHC class I-and class II-restricted epitopes, mostly of HPV-16 and HPV-18, have been reported (19,30,46,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69). Several HLA-A*0201-restricted HPV-16 E7 epitopes have already been applied in clinical trials, namely E7 [11][12][13][14][15][16][17][18][19][20] (32,33), E7 86 -93 (31)(32)(33)(34), and E7 [12][13][14][15][16][17][18][19][20] (34).…”

Section: Discussionmentioning

confidence: 99%

A Conserved E7-derived Cytotoxic T Lymphocyte Epitope Expressed on Human Papillomavirus 16-transformed HLA-A2+ Epithelial Cancers

Riemer

Keskin

Zhang

et al. 2010

Journal of Biological Chemistry

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Human Papillomavirus 16 (HPV-16) has been identified as the causative agent of 50% of cervical cancers and many other HPV-associated tumors. The transforming potential/tumor maintenance capacity of this high risk HPV is mediated by two viral oncoproteins, E6 and E7, making them attractive targets for therapeutic vaccines. Of 21 E6 and E7 peptides computed to bind HLA-A*0201, 10 were confirmed through TAP-deficient T2 cell HLA stabilization assay. Those scoring positive were investigated to ascertain which were naturally processed and presented by surface HLA molecules for CTL recognition. Because IFN␥ ELISpot frequencies from healthy HPV-exposed blood donors against HLA-A*0201-binding peptides were unable to identify specificities for tumor targeting, their physical presence among peptides eluted from HPV-16-transformed epithelial tumor HLA-A*0201 immunoprecipitates was analyzed by MS 3 Poisson detection mass spectrometry. Only one epitope (E7 11-19 ) highly conserved among HPV-16 strains was detected. This 9-mer serves to direct cytolysis by T cell lines, whereas a related 10-mer (E7 11-20 ), previously used as a vaccine candidate, was neither detected by MS 3 on HPV-transformed tumor cells nor effectively recognized by 9-mer specific CTL. These data underscore the importance of precisely defining CTL epitopes on tumor cells and offer a paradigm for T cellbased vaccine design.The transforming potential of human Papillomavirus (HPV), 4 first suspected in the 1970s, has now been firmly established both biologically and epidemiologically (1-3). The single most important variable linked to malignant transformation is persistent infection with one of the high-risk HPV types. The E6 and E7 proteins encoded by high-risk HPVs have transforming activities and functionally inactivate the p53 and retinoblastoma (Rb) tumor suppressor proteins, respectively (3, 4). HPV-16 is the most abundant high risk HPV and has been detected in Ͼ50% of cervical cancer cases and in most other HPV-induced tumors, such as carcinomas of the vagina, anus, vulva, penis, and oropharynx (3, 5, 6). Worldwide, high risk HPVs are thought to be responsible for Ͼ500,000 malignancies per year, representing more than 5% of human cancers (7).A major breakthrough in combating HPV-induced disease was the development of prophylactic vaccines to prevent HPV infection in previously unexposed individuals. These vaccines are based on virus-like particles consisting of the L1 capsid protein (8, 9). Virus-like particles resemble natural virions and are able to induce high titers of L1-neutralizing antibodies. Two vaccines, one against HPV-16, -18, -6, and -11 and another against HPV-16 and -18, were approved for clinical use in 2006 (10 -12). Although the impact of prophylactic HPV vaccination on the incidence of vaccine type HPV-associated disease and cancer is unquestionable over time, these vaccines have no therapeutic efficacy for established HPV infections. Antibodies neutralize virus particles only before infection. Moreover, as HPV capsid proteins are exc...

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Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

Cited by 24 publications

References 47 publications

HLA Class I Binding Promiscuity of the CD8 T-Cell Epitopes of Human Papillomavirus Type 16 E6 Protein

HLA Class I Binding Promiscuity of the CD8 T-Cell Epitopes of Human Papillomavirus Type 16 E6 Protein

A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells

A Conserved E7-derived Cytotoxic T Lymphocyte Epitope Expressed on Human Papillomavirus 16-transformed HLA-A2+ Epithelial Cancers

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