Identification of MAGE-3 Epitopes Presented by HLA-DR Molecules to CD4+ T Lymphocytes

Chaux, Pascal; Vantomme, Valérie; Stroobant, Vincent; Thielemans, Kris; Corthals, Jurgen; Luiten, Rosalie M.; Eggermont, Alexander M.M.; Boon, Thierry; Bruggen, Pierre van der

doi:10.1084/jem.189.5.767

Cited by 197 publications

(143 citation statements)

References 48 publications

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“…In retrospect, we would have arrived at similar results had we initiated our search for T cell reactivity using ex vivo-sensitized human lymphocytes similar to that of investigators who have identified MHC class II-restricted epitopes for MAGE-3 (23,24). By using DR4-IE Tg mice, we circumvented the need to sensitize human lymphocytes to a large number of peptides, allowed for the naturally processed, immunodominant epitope to be presented in vivo, and established the basis for a workable tumor treatment model.…”

Section: Discussionmentioning

confidence: 58%

“…Therefore, a need exists for the development of techniques useful in the identification of tumor-associated MHC class II-restricted epitopes in human cancers. While the targets of several CD4 ϩ T cells with potential anti-tumor activity have been identified (21)(22)(23)(24)(25)(26), no reliable, repeatable method for class II-restricted epitope identification has been established.…”

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confidence: 99%

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Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice

Touloukian

Leitner

Topalian

et al. 2000

The Journal of Immunology

115

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CD4+ T cells play a central role in the induction and persistence of CD8+ T cells in several models of autoimmune and infectious disease. To improve the efficacy of a synthetic peptide vaccine based on the self-Ag, gp100, we sought to provide Ag-specific T cell help. To identify a gp100 epitope restricted by the MHC class II allele with the highest prevalence in patients with malignant melanoma (HLA-DRB1*0401), we immunized mice transgenic for a chimeric human-mouse class II molecule (DR4-IE) with recombinant human gp100 protein. We then searched for the induction of CD4+ T cell reactivity using candidate epitopes predicted to bind to DRB1*0401 by a computer-assisted algorithm. Of the 21 peptides forecasted to bind most avidly, murine CD4+ T cells recognized the epitope (human gp10044–59, WNRQLYPEWTEAQRLD) that was predicted to bind best. Interestingly, the mouse helper T cells also recognized human melanoma cells expressing DRB1*0401. To evaluate whether human CD4+ T cells could be generated from the peripheral blood of patients with melanoma, we used the synthetic peptide h-gp10044–59 to sensitize lymphocytes ex vivo. Resultant human CD4+ T cells specifically recognized melanoma, as measured by tumor cytolysis and the specific release of cytokines and chemokines. HLA class II transgenic mice may be useful in the identification of helper epitopes derived from Ags of potentially great clinical utility.

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 99%

Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice

Touloukian

Leitner

Topalian

et al. 2000

The Journal of Immunology

115

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“…These antigens are recognized by autologous cytotoxic T-lymphocytes (CTLs), which are restricted by human leukocyte antigen (HLA) class I molecules, and some antigenic peptides have been identified (Van den Eynde et al, 1997). Furthermore, these antigens are also reported to induce class II restricted T-cell responses (Chaux et al, 1999;Manici et al, 1999). Some of these antigens are expressed in various tumours of different histological origins, but not in normal tissues other than testis.…”

Section: Introductionmentioning

confidence: 99%

Expression of multiple cancer-testis antigen genes in gastrointestinal and breast carcinomas

et al. 2001

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Summary Cancer-testis antigens (CTAs) such as MAGE are selectively expressed in various types of human neoplasms but not in normal tissues other than testis. This characteristic feature of CTAs makes them promising antigens for cancer-specific immunotherapy. A critical requirement for this therapy is identification of promising antigens. In this study, we investigated the expression of 6 genes recently identified by serological analysis of antigens by recombinant expression (SEREX) libraries: NY-ESO-1, LAGE-1, SCP-1, SSX-1, SSX-2, and SSX-4, in many surgical samples of gastrointestinal and breast carcinomas using reverse transcription-polymerase chain reaction. We found relatively high expression of SCP-1 (23.5%) and SSX-4 (20.6%) in gastric carcinoma, LAGE-1 (39.1%) and NY-ESO-1 (23.9%) in oesophageal carcinoma, and SCP-1 (34.1%) in breast carcinoma. We also found frequent synchronous expression with MAGE, including LAGE-1 (46.2%) in oesophageal carcinoma, SSX-4 (46.7%) in gastric carcinoma, and SCP-1 (38.3%) in breast carcinoma. Immunohistochemical analysis of the tumour samples expressing both MAGE-4 and NY-ESO-1 genes demonstrated differences in distribution between MAGE-4 and NY-ESO-1 in serial sections. We concluded that NY-ESO-1, LAGE-1, SCP-1 and SSX-4 genes may be promising candidates for cancer-specific immunotherapy in addition to MAGE, and that polyvalent cancer vaccines may be useful in cases of heterogeneous expressions of CTA genes in gastrointestinal and breast carcinomas.

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“…More than half of the remaining noncytotoxic CD4 þ clones released interferon-g on exposure to the melanoma line. Several other studies have reported isolation of HLA class II-restricted melanoma-specific CD4 þ CTLs, including clones recognising MAGE-3, NY-ESO1 and tyrosinase epitopes (Kobayashi et al, 1998;Chaux et al, 1999;Manici et al, 1999;Zarour et al, 2000). We isolated a CD4 þ HLA-DR11-restricted clone directed against an MAGE-3 epitope from one of our three normal donors.…”

Section: Discussionmentioning

confidence: 82%

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

Gottlieb

Lionello

et al. 2006

Br J Cancer

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Lymphodepletion and infusion of autologous expanded tumour-infiltrating lymphocytes is effective therapy for patients with malignant melanoma. Antitumour responses are likely to be mediated by HLA class I-and II-restricted immune responses directed at tumour antigens. We assessed whether the peripheral blood of normal HLA-matched siblings of patients with melanoma could be used to generate lymphocytes with antimelanoma activity for adoptive immunotherapy after allogeneic blood or marrow transplantation. Melanoma cell lines were derived from two donors and were used to stimulate the mononuclear cells of three HLAidentical siblings. CD4 þ clones dominated cultures. Of these, approximately half were directly cytotoxic towards recipient melanoma cells and secreted interferon-g in response to tumour stimulation. More than half of the noncytotoxic clones also secreted interferong after melanoma stimulation. No CD4 þ clones responded to stimulation with recipient haemopoietic cells. The majority of CD8 þ clones directly lysed recipient melanoma, but did not persist in long-term culture in vitro. No crossreactivity with recipient haemopoietic cells was observed. The antigenic target of one CD4 þ clone was determined to be an HLA-DR11-restricted MAGE-3 epitope. Antigenic targets of the remaining clones were not elucidated, but appeared to be restricted through a non-HLA-DR class II molecule. We conclude that the blood of allogeneic HLA-matched sibling donors contains melanoma-reactive lymphocyte precursors directed at tumour-associated antigens. Adoptive immunotherapy with unselected or ex vivo-stimulated donor lymphocytes after allogeneic stem cell transplantation has a rational basis for the treatment of malignant melanoma.

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Identification of MAGE-3 Epitopes Presented by HLA-DR Molecules to CD4+ T Lymphocytes

Cited by 197 publications

References 48 publications

Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice

Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice

Expression of multiple cancer-testis antigen genes in gastrointestinal and breast carcinomas

Generation of tumour-specific cytotoxic T-cell clones from histocompatibility leucocyte antigen-identical siblings of patients with melanoma

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