Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors

Matsumoto, Koji; Leggatt, Graham R.; Zhong, Jie; Liu, Xiaosong; Kluyver, Rachel L. de; Peters, Tania; Fernando, Germain J. P.; Liem, Amy; Lambert, Paul F.; Frazer, Ian H.

doi:10.1093/jnci/djh301

Cited by 59 publications

(86 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a murine model of skin grafting, we were able to mimic the immunosuppressive, hyperplastic lesions of HPV infection, which are a determinant of progression to cervical cancer. HPV16-E7-expressing skin transplanted onto sygeneic, immunocompetent hosts attracts inflammatory cell infiltrates; however, these grafts are not rejected (16,17). The underlying mechanism of immune resistance to these grafts is undefined.…”

mentioning

confidence: 99%

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

Mattarollo

Rahimpour

Choyce

et al. 2009

The Journal of Immunology

115

View full text Add to dashboard Cite

NKT cells can promote or inhibit adaptive immune responses. Cutaneous immunity is tightly regulated by cooperation between innate and adaptive immune processes, but the role of NKT cells in regulating cutaneous immunity is largely unknown. In this study, we show, in a mouse model, that skin-infiltrating CD1d-restricted NKT cells in HPV16-E7 transgenic hyperplastic skin produce IFN-γ, which can prevent rejection of HPV16-E7–expressing skin grafts. Suppression of graft rejection is associated with the accumulation of CD1dhi-expressing CD11c+F4/80hi myeloid cells in hyperplastic skin. Blockade of CD1d, removal of NKT cells, or local inhibition of IFN-γ signaling is sufficient to restore immune-mediated graft rejection. Thus, inhibition of NKT cell recruitment or function may enable effective immunity against tumor and viral Ags expressed in epithelial cells.

show abstract

mentioning

confidence: 99%

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

Mattarollo

Rahimpour

Choyce

et al. 2009

The Journal of Immunology

115

View full text Add to dashboard Cite

show abstract

“…Furthermore, immunisation with vaccines that are known to reject E7 producing transplantable tumours, also failed to reject E7 skin grafts (11,12). This result contrasts to similar skin-grafting experiments where other proteins are used as transgenes, e.g, ovalbumin protein (OVA) & human growth hormone: such grafts spontaneously reject within 20 days (13,14). These findings suggested that the fate of grafts is antigen dependant, and suggested the existence of a mechanism leading to E7 tolerance which could explain the failure of E7 therapeutic vaccination.…”

Section: Introductionmentioning

confidence: 93%

“…Grafts intact at day 200 post-surgery were retained as nonrejected. Skin graft rejection was assessed as described (14).…”

Section: Skinmentioning

confidence: 99%

Cervical Cancer-Associated Human Papillomavirus 16 E7 Oncoprotein Inhibits Induction of Anti-Cancer Immunity by a CD4+ T Cell Dependent Mechanism

et al. 2009

View full text Add to dashboard Cite

Attempts to develop therapeutic vaccines against cervical cancer have been proven difficult . One of the major causes of the failure is due to the use of the wrong mouse models based on transplantable tumours in testing the efficacy of vaccines. Now that a transgenic epithelial mouse model has been developed to closely mimic cervical cancer, the mechanisms needed to eliminate this type of cancer could be studied. The E7 oncoprotein of Human Papillomavirus (HPV) is the most expressed HPV protein in cervical cancers and its continuous production is essential to maintain the cancerous state and therefore the obvious target in the development of vaccines.Skin grafts expressing the HPV 16 E7 protein (E7 autografts) are not spontaneously rejected from an MHC matched immunocompetent host. Interestingly, simultaneous placement of an MHC mismatched skin (allograft) next to an E7 autograft results in the E7 autograft rejection. However when the allograft also expresses E7, the E7 autograft is rejected more slowly. Autograft rejection requires CD8 + T cells, and is accelerated by removal of CD4 + T cells after placement of the E7 expressing allograft, suggesting induction of an E7 specific CD4 + regulatory T cell population by the E7 expressing allograft. This observation may have implications in designing effective vaccines and immunotherapy against cervical cancers in women. 2Nature Precedings :

show abstract

“…The preparation of HPV16E7 protein has been previously described [28]. The H-2D b -restricted CTL epitope, HPV16 E7 49-57 [29], with the amino acid sequence RAHYNIVTF (E7 peptide), the H-2K b -restricted epitope, OVA 257-264 [30], with the amino acid sequence SIINFEKL, the H-2K b -restricted epitope, SVN 324-332 [31], with the amino acid sequence FAPGNYPAL, a polyepitope peptide containing all three CTL peptides without spacers, an HPV16E7 antibody epitope, with the amino acid sequence EIDGPAGQAEPDRAHYNIVTF, and an HPV16E7 CD4 epitope, with amino acid sequence QAEPDRAHYNIVTFCCKCD, were all purchased from Auspep Pty (Melbourne, Australia) with 470% purity.…”

Section: Reagentsmentioning

confidence: 99%

“…Serum antibodies including isotype-specific antibodies against HPV16E7 were measured by ELISA [35] and IFN-g levels in culture supernatants were assessed by capture ELISA [28] as previously described. Serum antibody titers were calculated as the highest dilution of post-immunization serum producing an absorbance value greater than three standard deviations above the absorbance value for pre-immunization serum from that group of mice.…”

Section: Generation Of E7-specific Tcr-b Transgenic Micementioning

confidence: 99%

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

et al. 2009

View full text Add to dashboard Cite

The role of thymic versus peripheral epithelium in the regulation of the antigen-specific CD8 T-cell repertoire is still largely unresolved. We generated TCR-b chain transgenic mice in which an increased frequency of peripheral CD8 T cells recognizes an epitope from a viral oncoprotein (HPV16E7) in the context of H-2D b MHC class I. When T cells from these mice developed through the thymus of mice expressing functional E7 protein from a keratin 14 promoter, no major perturbation to transgenic T-cell development in the thymus was observed in these double-transgenic mice. In contrast, peripheral CD8 T-cell responses in the single-transgenic, K14E7 mice, including those unrelated to E7 antigen, are reduced whereas CD4 T-cell responses and antibody production are unchanged in these mice. Peripheral non-responsiveness among CD8 T cells was mediated largely by CD4 1 CD25 1 T cells. This suggested that epithelium expressing HPV16E7 protein inducesTreg that specifically down-regulate CD8 T-cell responses in the periphery. This may have important consequences for the treatment of cervical pre-cancers and provides a model for understanding differential suppression of T and B lymphocyte subsets by Treg.Key words: Skin . Suppression . T cells . Thymus . Transgenic mice IntroductionT-cell development starts in the thymus, where lymphocytes expressing TCR recognize self-peptides bound to MHC class I. Immature T cells are either deleted if the affinity of interaction is high (negative selection) or retained for export to the periphery if the affinity is low (positive selection). Medullary epithelial cells and DC are thought to induce negative selection whereas cortical epithelial cells positively select the T-cell repertoire [1][2][3][4]. Evidence for the role of cortical epithelial cells in positive selection comes from studies of MHC expression driven from a keratin 14 (K14) promoter in otherwise MHC-deficient mice [5,6]. In contrast, expression of protein and peptide antigens in K14 1 thymic epithelium results in the deletion of antigen-specific CD8 T cells and the editing of the transgenic TCR [7][8][9]. Consequently, depending on the model, T cells are either positively selected or negatively selected after contact with thymic epithelium. HPV16E7 is one of the key oncogenes expressed during progression to cervical cancer: the protein is expressed in the epithelial cells of the cervix during human papillomavirus (HPV) infection and subsequent cancer development [10]. Given that mice cannot be naturally infected with HPV, human cervical cancer has been modeled in mice by transgenic expression of HPV16E7 leading to E7 expression in the thymus and peripheral epithelial sites, e.g. skin keratinocytes [11,12]. The first such K14E7 transgenic mice were generated on an FVB mouse 481background that failed to present the dominant CD8 T-cell peptide identified in the C57BL/6 background [12]. Subsequently, K14E7FVB Â C57 F1 mice were generated and shown to have poor CD8 T-cell responses that were attributable to the induction of per...

show abstract

Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors

Cited by 59 publications

References 36 publications

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

Cervical Cancer-Associated Human Papillomavirus 16 E7 Oncoprotein Inhibits Induction of Anti-Cancer Immunity by a CD4+ T Cell Dependent Mechanism

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

Contact Info

Product

Resources

About

Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors

Cited by 59 publications

References 36 publications

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

Invariant NKT Cells in Hyperplastic Skin Induce a Local Immune Suppressive Environment by IFN-γ Production

Cervical Cancer-Associated Human Papillomavirus 16 E7 Oncoprotein Inhibits Induction of Anti-Cancer Immunity by a CD4+ T Cell Dependent Mechanism

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4+CD25+ T cells

Contact Info

Product

Resources

About

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells