Kowalewski Daniel J, Schuster Heiko, Backert Linus, Berlin Claudia, Kahn Stefan, Kanz Lothar, Salih Helmut R, Rammensee Hans-Georg, Stevanovic Stefan, Stickel Juliane Sarah
Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany;
Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen 72076, Germany; Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tübingen, Tübingen 72076, Germany;
Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):E166-75. doi: 10.1073/pnas.1416389112. Epub 2014 Dec 29.
The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
临床有效免疫检查点抑制剂的突破性发展表明了基于T细胞的免疫疗法有效治疗恶性肿瘤的潜力。一个尚存的挑战是增强并引导抗癌免疫反应的特异性，例如通过治疗性疫苗接种或过继性T细胞转移。通过分析原发性慢性淋巴细胞白血病（CLL）自然呈递的HLA I类和II类配体格局，我们基于其在白血病细胞HLA配体组中的独特且频繁出现，划定了一类新型肿瘤相关T细胞抗原。这些抗原在CLL的不同阶段和突变亚型中得到验证，并发现它们在接受标准化疗/免疫治疗的患者的HLA配体组中大量存在。我们证明这些抗原仅在CLL患者中得到特异性免疫识别，其在CLL配体组中的出现频率与患者T细胞的免疫识别频率相关。此外，回顾性生存分析显示，对这些抗原产生免疫反应的患者具有生存优势。这些结果直接表明这些非突变自身肽是病理生理学相关的肿瘤抗原，并鼓励将其应用于癌症免疫治疗。
