Altvater Bianca, Kailayangiri Sareetha, Theimann Nadine, Ahlmann Martina, Farwick Nicole, Chen Christiane, Pscherer Sibylle, Neumann Ilka, Mrachatz Gabriele, Hansmeier Anna, Hardes Jendrik, Gosheger Georg, Juergens Heribert, Rossig Claudia
Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer Campus 1, 48149, Münster, Germany.
Cancer Immunol Immunother. 2014 Oct;63(10):1047-60. doi: 10.1007/s00262-014-1574-3. Epub 2014 Jun 28.
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.
播散性或复发性尤因肉瘤（EwS）在大多数患者中仍然是致命的。预防传统治疗后复发的一种有前景的方法是建立肿瘤抗原特异性免疫控制。针对肿瘤的高效且特异性的T细胞记忆取决于具有针对肿瘤过度表达的靶抗原的天然特异性的稀有T细胞的扩增。EwS中的候选抗原包括前列腺六跨膜上皮抗原1（STEAP1）、人类癌胚抗原X抗原家族成员1（XAGE1）和黑色素瘤优先表达抗原（PRAME）。在这里，我们通过IFN-γ酶联免疫斑点分析筛选正常供体和EwS患者中是否存在与这些抗原的重叠肽库反应的循环T细胞。22名健康供体中的大多数缺乏针对STEAP1、XAGE1和PRAME的可检测到的记忆T细胞反应。此外，在血液和骨髓中对这些抗原特异性T细胞的体外检测仅限于少数EwS患者，并且需要非特异性T细胞预刺激。使用专业抗原呈递细胞和优化的细胞因子刺激通过体外致敏有效地、可靠地产生了针对肿瘤相关抗原的细胞毒性T细胞；然而，这些T细胞未能与靶细胞加工的天然抗原以及表达该抗原的EwS细胞相互作用。我们得出结论，即使在优化条件下，EwS相关抗原也无法诱导有效的T细胞受体（TCR）介导的抗肿瘤免疫反应。基于TCR工程的策略可能提供一种更有效的手段来操纵T细胞免疫以靶向消除肿瘤细胞。
