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

Höhn, Hanni; Pilch, Henryk; Günzel, Susanne; Neukirch, Claudia; Freitag, Kirsten; Necker, Antje; Maeurer, Markus

doi:10.1128/jvi.74.14.6632-6636.2000

Cited by 38 publications

(17 citation statements)

References 28 publications

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“…Indeed, cervical tumors are infiltrated by lymphocytes (16) and both CD8+ and CD4+ T cells isolated from such tumors are able to recognize the E6 and E7 tumor antigens (17,18). Furthermore, we showed that 43% of the isolated tumor-infiltrating lymphocyte (TIL) and tumordraining lymph node cell (TDLNC) cultures from a large cohort of HPV16-or HPV18-positive patients contained T cells specific only for the E6 and/or E7 peptides corresponding to the HPV type present in the tumor (3).…”

Section: Introductionmentioning

confidence: 99%

An Unexpectedly Large Polyclonal Repertoire of HPV-Specific T Cells Is Poised for Action in Patients with Cervical Cancer

et al. 2010

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The diversity and extent of the local tumor-specific T-cell response in a given individual is largely unknown. We have performed an in-depth study of the local T-cell repertoire in a selected group of patients with cervical cancer, by systematic analyses of the proportion, breadth, and polarization of human papillomavirus (HPV) E6/E7-specific T cells within the total population of tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC). Isolated T cells were stimulated with sets of overlapping E6 and E7 peptides and analyzed by multiparameter flow cytometry with respect to activation, cytokine production, and T-cell receptor Vβ usage. HPV-specific CD4+ and CD8+ T-cell responses were detected in TIL and TDLNC and their relative contribution varied between <1% and 66% of all T cells. In general, these HPV-specific responses were surprisingly broad, aimed at multiple E6 and E7 epitopes and involved multiple dominant and subdominant T-cell receptor Vβs per single peptide-epitope. In most patients, only few IFNγ-producing T cells were found and the amount of IFNγ produced was low, suggesting that these are poised T cells, rendered functionally inactive within the tumor environment. Importantly, stimulation of the TIL and TDLNC with cognate antigen in the presence of commonly used Toll-like receptor ligands significantly enhanced the effector T-cell function. In conclusion, our study suggests that within a given patient with HPV-specific immunity many different tumor-specific CD4+ and CD8+ T cells are locally present and poised for action. This vast existing local T-cell population is awaiting proper stimulation and can be exploited for the immunotherapy of cancer.

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Section: Introductionmentioning

confidence: 99%

An Unexpectedly Large Polyclonal Repertoire of HPV-Specific T Cells Is Poised for Action in Patients with Cervical Cancer

et al. 2010

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“…These proteins, E6 and E7, are constitutively expressed because they are required to maintain the malignant phenotype (9). The tumor can be infiltrated by lymphocytes (10,11), and both CD8 + and CD4 + T cells isolated from tumors are able to recognize the E6 and E7 tumor antigens (12)(13)(14) 5 as well as to kill tumor cells in vitro (15,16). Tumorspecific T cells, directed against the two HPV-encoded oncoproteins, can be detected in the peripheral blood of f50% of the patients albeit at low levels (17)(18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

High Number of Intraepithelial CD8+ Tumor-Infiltrating Lymphocytes Is Associated with the Absence of Lymph Node Metastases in Patients with Large Early-Stage Cervical Cancer

Piersma

Jordanova²,

Poelgeest³

et al. 2007

Cancer Research

379

249

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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

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“…To validate this assumption, we took advantage of the HPV 68-positive cervical cancer cell line ME180. This cell line is able to present a DR4-restricted HPV E7 epitope to CD41 T cells 32 and allows one to combine expression analysis of MHC class II antigen presentation components with functional T-cell recognition. Immunofluorescence revealed constitutive expression of CIITA, HLA-DR, DMA, DMB and CLIP in the majority of tumor cells (Fig.…”

Section: Differential Mhc Class II Component Expression and Localizatmentioning

confidence: 99%

Differential MHC class II component expression in HPV‐positive cervical cancer cells: Implication for immune surveillance

Zehbe¹,

Höhn²,

Pilch³

et al. 2005

Intl Journal of Cancer

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Effective eradication of human papillomavirus (HPV)-positive tumors may require CD81 and CD41 T-cell-mediated immune responses. Ectopic expression of MHC class II surface molecules has been described in the context of cervical cancer, but coexpression with other components of the MHC class II antigen presentation pathway has not been addressed. We have evaluated the MHC class II antigen presentation pathway in malignant squamous epithelium of HPV1 cervical cancer lesions by in situ costaining HLA-DR with CLIP or DMA/DMB. Cervical cancer cells exhibit 3 MHC class II phenotypes: (i) DR1/CLIP1 or DM1; (ii) DR1/CLIP-or DM-; and (iii) DR-/CLIP1 or DM1. The identical profile has been identified in HPV1 ME180 cells, which serve as a target for HLA-DR4-restricted and HPV68, E7-specific CD41 T cells. IFN-c pretreatment of ME180 cells, associated with differential trafficking of MHC class II molecules, is necessary for effective T-cell recognition. Although proinflammatory cytokines may facilitate MHC class II-restricted antigen recognition in tumor cells, different phenotypes of the MHC class II antigen presentation pathway may be associated with evasion from CD41-mediated cellular immune responses. ' 2005 Wiley-Liss, Inc.

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

Cited by 38 publications

References 28 publications

An Unexpectedly Large Polyclonal Repertoire of HPV-Specific T Cells Is Poised for Action in Patients with Cervical Cancer

An Unexpectedly Large Polyclonal Repertoire of HPV-Specific T Cells Is Poised for Action in Patients with Cervical Cancer

High Number of Intraepithelial CD8+ Tumor-Infiltrating Lymphocytes Is Associated with the Absence of Lymph Node Metastases in Patients with Large Early-Stage Cervical Cancer

Differential MHC class II component expression in HPV‐positive cervical cancer cells: Implication for immune surveillance

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