title: Common Ewing sarcoma-associated antigens fail to induce natural T cell responses in both patients and healthy individuals.
abstract: Disseminated or relapsed Ewing sarcoma (EwS) has remained fatal in the majority of patients. A promising approach to preventing relapse after conventional therapy is to establish tumor antigen-specific immune control. Efficient and specific T cell memory against the tumor depends on the expansion of rare T cells with native specificity against target antigens overexpressed by the tumor. Candidate antigens in EwS include six-transmembrane epithelial antigen of the prostate-1 (STEAP1), and the human cancer/testis antigens X-antigen family member 1 (XAGE1) and preferentially expressed antigen in melanoma (PRAME). Here, we screened normal donors and EwS patients for the presence of circulating T cells reactive with overlapping peptide libraries of these antigens by IFN-γ Elispot analysis. The majority of 22 healthy donors lacked detectable memory T cell responses against STEAP1, XAGE1 and PRAME. Moreover, ex vivo detection of T cells specific for these antigens in both blood and bone marrow were limited to a minority of EwS patients and required nonspecific T cell prestimulation. Cytotoxic T cells specific for the tumor-associated antigens were efficiently and reliably generated by in vitro priming using professional antigen-presenting cells and optimized cytokine stimulation; however, these T cells failed to interact with native antigen processed by target cells and with EwS cells expressing the antigen. We conclude that EwS-associated antigens fail to induce efficient T cell receptor (TCR)-mediated antitumor immune responses even under optimized conditions. Strategies based on TCR engineering could provide a more effective means to manipulating T cell immunity toward targeted elimination of tumor cells.
authors: Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 48149, Münster, Germany.
authors: Bianca
authors: B
authors: Altvater
authors: Sareetha
authors: S
authors: Kailayangiri
authors: Nadine
authors: N
authors: Theimann
authors: Martina
authors: M
authors: Ahlmann
authors: Nicole
authors: N
authors: Farwick
authors: Christiane
authors: C
authors: Chen
authors: Sibylle
authors: S
authors: Pscherer
authors: Ilka
authors: I
authors: Neumann
authors: Gabriele
authors: G
authors: Mrachatz
authors: Anna
authors: A
authors: Hansmeier
authors: Jendrik
authors: J
authors: Hardes
authors: Georg
authors: G
authors: Gosheger
authors: Heribert
authors: H
authors: Juergens
authors: Claudia
authors: C
authors: Rossig
mesh_terms: D000293:Adolescent; D000328:Adult; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D020014:K562 Cells; D008297:Male; D010088:Oxidoreductases / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D012512:Sarcoma, Ewing / Q000097:blood / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; C404944:PRAME protein, human; C413656:XAGE1A protein, human; D010088:Oxidoreductases; C432763:STEAP1 protein, human