The status of HPV16-specific T-cell reactivity in health and disease as a guide to HPV vaccine development

Burg, Sjoerd H. van der; Jong, Annemieke de; Welters, Marij J.P.; Offringa, Rienk; Melief, Cornelis J.M.

doi:10.1016/s0168-1702(02)00196-x

Cited by 29 publications

(25 citation statements)

References 69 publications

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“…Peptide was added at 50 lg/ml in DMSO and incubated overnight at 37°C. For HLA-A2 binding, a known HLA-A2 binding peptide, M1 [58][59][60][61][62][63][64][65][66] (GILGFVTFL), 36 and a known non-binding peptide HPV31 E7 [11][12][13][14][15][16][17][18][19][20] analogue (YILVQPEAT, unpublished observations) were used as controls. For RMA-S cells (expressing K b and D b ), the D b binding HPV16 E7 [49][50][51][52][53][54][55][56] peptide (RAHY-NIVTF) 33 and the non-D b /K b binding M1 [58][59][60][61][62][63][64][65][66] were used as controls.…”

Section: T2/rma-s Binding Assaysmentioning

confidence: 99%

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Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

McCarthy

Youde

Man

2006

Intl Journal of Cancer

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Although human papillomavirus (HPV) types 16 and 18 are the most common types associated with cervical cancer worldwide, other related HPV types such as HPV 35, 45 and 58 have significant prevalence in geographically distinct populations. For development of global prophylactic and therapeutic vaccine strategies, it is important to study immune responses against these viruses and to define the degree of cross-reactivity between related HPV types. To investigate the potential for T cell cross-reactivity after vaccination, HLA-A2/K b transgenic mice were immunised with DNA plasmid constructs containing HPV18 and 45 E6 and E7.Splenocytes from immunised mice were tested in direct ELIspot assays against overlapping pools of HPV 18 peptides. Immunisation with either HPV18 or HPV45 E6 DNA produced dominant T cell responses against an epitope (KCIDFYSRI) that was shared between HPV18 and HPV45. This peptide was shown to bind to HLA-A*0201 but not D b or K b molecules on the cell surface. Furthermore this peptide was shown to be immunogenic in vitro to human T cells from 2 out of 3 HLA-A2 1 healthy donors. Collectively, these results demonstrate that HPV 18 and 45 E6 DNA vaccines are immunogenic in mice and demonstrate that cross-reactive T cell responses against closely related HPV types can be induced in vivo. The use of the HLA-A2/K b transgenic mice allowed definition of an HLA-A*0201 binding peptide epitope that would have been rejected on the basis of predicted major histocompatibility complex binding affinity. ' 2005 Wiley-Liss, Inc.Key words: HPV; CTL; cervical cancer; epitope; cross-reactivity Human papillomavirus (HPV) infection is strongly associated with the development of virtually all cervical cancers, 1 and some head, neck 2 and skin cancers. 3 Cervical cancer is the 2nd leading cause of female cancer mortality worldwide, with an estimated 400,000 new cases every year. 4 The global burden of cervical cancer has lead to much research into prophylactic and therapeutic vaccines. Despite encouraging recent data with prophylactic vaccines, 5 there is still a need to develop therapeutic approaches for cancer and to address the considerable burden of recurrent HPVassociated anogenital neoplasias.Cell-mediated immunity is important in the control of HPV infection, as HPV-associated cervical lesions are more prevalent in immunosuppressed individuals. 6,7 Furthermore, regression of HPV-induced warts is associated with lymphocytic infiltration in man and animal models. 8 CD8 1 cytotoxic T lymphocytes (CTL) are known to protect against persistent viruses, 9 but importantly can also mediate tumour regression in animal models 10,11 and in a limited number of clinical studies in man. 12-14 CD8 1 CTL recognise endogenously processed peptides bound to major histocompatibility complex (MHC) class I molecules on tumour cells. 15 For oncogenic HPV types, the intracellular E6 and E7 proteins provide attractive targets because of their persistent and obligate expression in tumour cells. 16 Therapeutic approaches have largely ta...

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Section: T2/rma-s Binding Assaysmentioning

confidence: 99%

“…18) and human studies have investigated immune responses against HPV16. 19 By contrast immune responses against HPV18, a type associated with aggressive forms of cervical adenocarcinoma has been little studied. Cell-mediated immunity against other types such as HPV31, 52 and 58, which are also associated with cancer, 1 have not been studied at all.…”

mentioning

confidence: 99%

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

McCarthy

Youde

Man

2006

Intl Journal of Cancer

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“…Cytotoxic T cell (CTL) and T helper activity specific for E6 and E7 of HPV-16 and HPV-18 (the 2 most common HPV types) have been demonstrated in the peripheral blood of patients with (pre)malignant cervical neoplasia and healthy controls. [4][5][6][7][8][9][10][11][12] It has been suggested that spontaneous regression of CIN lesions might be associated with cell-mediated immune responses against the E6 and E7 oncoproteins of HPV. [4][5][6][7][8][9][10][11] However, the relative contribution of E6 and E7 specific cellular immune responses to the prevention or the eradication of (pre)malignant cervical neoplasia is debated.…”

mentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11][12] It has been suggested that spontaneous regression of CIN lesions might be associated with cell-mediated immune responses against the E6 and E7 oncoproteins of HPV. [4][5][6][7][8][9][10][11] However, the relative contribution of E6 and E7 specific cellular immune responses to the prevention or the eradication of (pre)malignant cervical neoplasia is debated. 4,11 Recent reports suggest that the failure to develop a potent T helper type 1 response specific for the oncoprotein E6 and the early protein E2 of HPV might be responsible for the development of high grade CIN lesions and cervical cancer.…”

mentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11] However, the relative contribution of E6 and E7 specific cellular immune responses to the prevention or the eradication of (pre)malignant cervical neoplasia is debated. 4,11 Recent reports suggest that the failure to develop a potent T helper type 1 response specific for the oncoprotein E6 and the early protein E2 of HPV might be responsible for the development of high grade CIN lesions and cervical cancer. 7,13,14 The observation that strong proliferative T cell responses specific for HPV-16 E7 peptides are found more often in patients with regression of premalignant cervical lesions 9 also indicates the importance of cell-mediated immune responses against E7 in the prevention of high-grade premalignant cervical neoplasia.…”

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Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia

Visser

Baarle

Hoogeboom

et al. 2006

Intl Journal of Cancer

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It has been suggested that local invasive procedures may alter the natural course of (pre)malignant cervical disease. This could be due to partial excision of the lesions, or via induction of cellular immunity against human papillomavirus (HPV) by the local invasive procedures. We studied the influence of local invasive procedures on HPV-16 E7 specific immune responses in patients with different grades of cervical intra-epithelial neoplasia (CIN) and different stages of cervical cancer. Blood was obtained at intake and after invasive procedures from patients with CIN or cervical cancer. Antigen specific T-cell responses were measured by IFN-c ELISPOT analysis, after stimulation with recombinant HPV-16 E7 protein. As expected, HPV-16 E7 specific IFN-c T cell responses were more frequent in HPV-16 DNA positive patients compared with that in HPV-16 DNA negative patients (39/50 vs. 16/36, (p 5 0.006, v 2 test). After invasive procedures, a small number of HPV-16 DNA positive CIN patients, but a considerable proportion of HPV-16 DNA positive cervical cancer patients, showed an enhancement of T cell responses against HPV-16 E7. Induction of T cell reactivity was most pronounced in cervical cancer patients who had undergone previous invasive procedures. Both CD4 1 and CD8 1 T cells showed E7 specific IFN-c production upon in-vitro stimulation. Our study shows that invasive procedures may enhance HPV-specific cell-mediated immunity in a considerable number of patients with cervical cancer, but in only a minority of CIN patients. Our data indicate that invasive procedures should be considered as possible confounding factors when analyzing the effectiveness of therapeutic immunization studies, especially, when induction of HPV-specific immune responses is used as intermediate end-point. ' 2005 Wiley-Liss, Inc.Key words: cervical cancer; IFN-g; HPV; CD4 1 T cell; CD8 1 T cell Infection with oncogenic human papillomavirus (HPV) plays an important role in cervical carcinogenesis, and HPV DNA can be detected in 90-100% of all cervical cancers. 1,2 The majority of women infected with oncogenic HPV types do not develop cervical intraepithelial neoplasia (CIN) or cervical cancer but clear their HPV infection. The immune system plays an important role herein, as demonstrated by the observation that immunocompromised women, such as AIDS-patients, more often fail to clear an HPV infection and have an increased risk to develop cervical cancer. 3 The E6 and E7 transforming oncoproteins of HPV play a crucial role in the transformation and maintenance of the malignant phenotype, and therefore, these proteins are the ideal candidates for tumor-specific cervical cancer immunotherapy. Cytotoxic T cell (CTL) and T helper activity specific for E6 and E7 of HPV-16 and HPV-18 (the 2 most common HPV types) have been demonstrated in the peripheral blood of patients with (pre)malignant cervical neoplasia and healthy controls. [4][5][6][7][8][9][10][11][12] It has been suggested that spontaneous regression of CIN lesions might be associated with...

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CD4⁺ T cell immunity against the human papillomavirus‐18 E6 transforming protein in healthy donors: identification of promiscuous naturally processed epitopes

et al. 2005

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Infection by 'high-risk' human papillomaviruses (HPV) is associated with the development of neoplastic lesions. HPV-18 is responsible for a very aggressive form of cancer and poor survival. As for other HPV types, immune surveillance has probably a role in the control of the infection. However, very little is known on HPV-18 immunogenicity. CD4 + T cells from 16 healthy donors were tested ex vivo for reactivity to synthetic peptides corresponding to 3 sequences on the HPV-18 E6 transforming protein predicted by bioinformatics as promiscuous HLA-DR ligands, and to the recombinant E6 protein. We found 3 donors with CD4 + T cells that specifically proliferated in the presence of HPV-18 E6 antigens and produced IFN-c in the presence of the E6 protein. We then propagated CD4 + T cell lines and clones from the responsive subjects to better characterize the recognized sequences. We show that E6 52-66 and E6 97-111 are indeed promiscuous and, most importantly, they contain naturally processed epitopes. Collectively, our data indicate that healthy donors may develop spontaneous CD4 immunity against HPV-18 E6 epitopes, thus strongly suggesting the potential for this protein to elicit in the host a natural productive immune response.

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The status of HPV16-specific T-cell reactivity in health and disease as a guide to HPV vaccine development

Cited by 29 publications

References 69 publications

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia

CD4⁺ T cell immunity against the human papillomavirus‐18 E6 transforming protein in healthy donors: identification of promiscuous naturally processed epitopes

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The status of HPV16-specific T-cell reactivity in health and disease as a guide to HPV vaccine development

Cited by 29 publications

References 69 publications

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia

CD4+ T cell immunity against the human papillomavirus‐18 E6 transforming protein in healthy donors: identification of promiscuous naturally processed epitopes

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CD4⁺ T cell immunity against the human papillomavirus‐18 E6 transforming protein in healthy donors: identification of promiscuous naturally processed epitopes