title: MAGE-C2-Specific TCRs Combined with Epigenetic Drug-Enhanced Antigenicity Yield Robust and Tumor-Selective T Cell Responses.
abstract: Adoptive T cell therapy has shown significant clinical success for patients with advanced melanoma and other tumors. Further development of T cell therapy requires improved strategies to select effective, yet nonself-reactive, TCRs. In this study, we isolated 10 TCR sequences against four MAGE-C2 (MC2) epitopes from melanoma patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. We introduced these TCRs into T cells, pretreated tumor cells of different histological origins with the epigenetic drugs azacytidine and valproate, and tested tumor and self-reactivities of these TCRs. Pretreatment of tumor cells upregulated MC2 gene expression and enhanced recognition by T cells. In contrast, a panel of normal cell types did not express MC2 mRNA, and similar pretreatment did not result in recognition by MC2-directed T cells. Interestingly, the expression levels of MC2, but not those of CD80, CD86, or programmed death-ligand 1 or 2, correlated with T cell responsiveness. One of the tested TCRs consistently recognized pretreated MC2(+) cell lines from melanoma, head and neck, bladder, and triple-negative breast cancers but showed no response to MHC-eluted peptides or peptides highly similar to MC2. We conclude that targeting MC2 Ag, combined with epigenetic drug-enhanced antigenicity, allows for significant and tumor-selective T cell responses.
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and a.kunert@erasmusmc.nl j.debets@erasmusmc.nl.
authors.forename: Andre
authors.initials: A
authors.lastname: Kunert
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and.
authors.forename: Mandy
authors.identifier: 0000-0001-9679-1094
authors.initials: M
authors.lastname: van Brakel
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and.
authors.forename: Sabine
authors.initials: S
authors.lastname: van Steenbergen-Langeveld
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and.
authors.forename: Marvin
authors.initials: M
authors.lastname: da Silva
authors.affiliation: de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and.
authors.forename: Cor
authors.identifier: 0000-0002-6887-1377
authors.initials: C
authors.lastname: Lamers
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and a.kunert@erasmusmc.nl j.debets@erasmusmc.nl.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001374:Azacitidine / Q000494:pharmacology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C497964:CD86 protein, human; D018984:Epitopes, T-Lymphocyte; C405429:MAGEC2 protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D014635:Valproic Acid; D001374:Azacitidine