Infiltration of cervical cancer tissue with human papilloma virus-specific cytotoxic T-lymphocytes

Evans, Elin; Man, Stephen; Evans, Alan W.; Borysiewicz, Leszek K.

doi:10.1016/s0165-2478(97)88693-2

Cited by 89 publications

(134 citation statements)

References 26 publications

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“…3 Indeed, while the majority of sexually active women become infected with HPV, only a minority develops premalignant cervical lesions or cervical cancer. 4 In these patients, as expected, HPVspecific CTL activity is generally low, 5,6 suggesting that they have mounted a certain degree of immunological tolerance or ignorance for the HPV-derived antigens. It is possible that this tolerance arises peripherally at the level of the epithelial keratinocytes, the target cells for HPV.…”

supporting

confidence: 65%

“…For example, expression of HPV E6 and E7 protein prevents the immunoregulatory effects of IFN-a-and IFN-b-mediated antiviral responses. 20 It is furthermore observed that women with cervical cancer develop poor levels of E7-specific CTLs in response to the developing tumor 5,6 or to an E7 vaccine. 21 This poor cellular immune response may be caused by the expression of E7 in epithelial cells lacking costimulation, which may lead not only to immunosuppression but also to immunological tolerance.…”

mentioning

confidence: 99%

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Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

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supporting

confidence: 65%

mentioning

confidence: 99%

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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“…Screening by the use of a long synthetic 20mer peptide library allowed us to identify an epitope that would not have been predicted with high priority by the computer program. The lack of response to the 20mer HPV18 E7 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] that includes the high affinity binding peptide HPV18 E7 7-15 described by Rudolf et al 24 would have excluded this potential epitope from further analysis as an irrelevant epitope. Consequently, we never found a response to this epitope.…”

Section: Discussionmentioning

confidence: 99%

“…In this library, consequently, all possible epitope sequences of the HPV18 E7 were represented. Sequences are: HPV18 E7 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] , p44 (MHGP-KATLQDIVLHLEPQNE); HPV18 E7 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] , p45 (VLHLEPQNE-IPVDLLCHEQL); HPV18 E7 , p46 (VDLLCHEQLSDSEEEN-DEID); HPV18 E7 34 -53 , p47 (SEEENDEIDGVNHQHLPARR); HPV18 E7 [45][46][47][48][49][50][51][52][53]…”

Section: Peptides and Proteinsmentioning

confidence: 99%

“…13 In tumors HPV16 E7 antigen-specific tumor infiltrating lymphocytes have been demonstrated. 14 Obviously, in cervical cancer patients the immune the response to HPV-transformed cells is prevented by strategies of the virus and deficiencies of the host. 15 Immunotherapeutic strategies attempt to break this blockade and to elicit an immune response, which can lead to tumor regression.…”

mentioning

confidence: 99%

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Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Kather

Ferrara

Nonn

et al. 2003

Intl Journal of Cancer

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Immunotherapy of HPV-associated disease such as cervical cancer is moving from preclinical investigation to clinical trials. The viral oncoproteins E6 and E7 are ideal target antigens because their expression is mandatory in HPVtransformed tumor cells. T cells are the most important effector cells for therapeutic vaccination strategies. Therefore, the identification and characterization of HPV E6 and E7 T cell epitopes is necessary. Methods to date rely on screening for immunogenicity of peptides predicted by algorithms. Presentation of the identified peptides on tumor cells, however, needs to be confirmed. In our study, we have improved the method to identify peptide epitopes of HPV18 E7 that are actually presented by tumor cells. We induced allogeneic T-cell lines by stimulation with HPV18-positive, CD80 and HLA-A*0201 transfected cervical cancer cells. Sensitized T cells were probed against an array of a HPV18 E7 20mer peptide-library. We found specific reactivity to one of the 20mer peptides. This sequence was then screened via algorithms for putative epitopes. One putative HLA-A2 restricted epitope was confirmed to bind to HLA-A2, to be immunogenic and to induce IFN␥-release in ELISpot assays. Epitope-specific T cells were cytolytic toward autologous peptide pulsed targets and HPV18 transformed tumor cells. The identification of epitope-specific T cells in tumor infiltrating lymphocytes of a HPV18-positive HLA-matched cervical cancer patient suggests an in vivo relevance of the identified epitope. We suggest that our approach is advantageous over conventional methods, because it yields candidate peptides that are relevant CTL epitopes that are expressed, processed and presented by tumor cells.

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Radiation-enhanced expression of E6/E7 transforming oncogenes of human papillomavirus-16 in human cervical carcinoma

Santin

Hermonat

Ravaggi

et al. 1998

Cancer

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Infiltration of cervical cancer tissue with human papilloma virus-specific cytotoxic T-lymphocytes

Cited by 89 publications

References 26 publications

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination

Radiation-enhanced expression of E6/E7 transforming oncogenes of human papillomavirus-16 in human cervical carcinoma

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Infiltration of cervical cancer tissue with human papilloma virus-specific cytotoxic T-lymphocytes

Cited by 89 publications

References 26 publications

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Identification of a naturally processed HLA‐A*0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro vaccination

Radiation-enhanced expression of E6/E7 transforming oncogenes of human papillomavirus-16 in human cervical carcinoma

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Identification of a naturally processed HLA‐A0201 HPV18 E7 T cell epitope by tumor cell mediated in vitro* vaccination