期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：2
页码：E166-E175
DOI：10.1073/pnas.1416389112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceEffective cancer immunotherapy relies on specific immune recognition of tumor-associated and tumor-specific antigens. In chronic lymphocytic leukemia (CLL), the highly variable course of disease implicates an underlying mechanism of tumor control by the immune system. In this study, we directly analyzed the landscape of naturally presented CLL antigens and identified targets conveying immune protection. These novel antigens might be valuable both for patient stratification and for inducing therapeutic antitumor immunity. Taken together, we demonstrate that CLL is subject to spontaneous T-cell responses targeting nonmutated antigens, which are associated with improved patient survival and provide novel options for the immunotherapy of CLL. 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.
