HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL)

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.

Keywords: HLA; cancer immunotherapy; chronic lymphocytic leukemia; therapeutic vaccination; tumor-associated antigens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Antigen Presentation
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology
  • Female
  • HLA Antigens / metabolism*
  • Humans
  • Immunity, Innate
  • Immunotherapy / methods*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
  • Ligands
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Vaccines, Subunit / genetics
  • Vaccines, Subunit / immunology


  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Neoplasm
  • Cancer Vaccines
  • HLA Antigens
  • Ligands
  • Vaccines, Subunit