Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid-immunoglobulin complexes in humans

J Clin Invest. 2011 Apr;121(4):1574-84. doi: 10.1172/JCI44581. Epub 2011 Mar 14.


Donor lymphocyte infusion (DLI), whereby donor mononuclear cells are infused into patients, is one of the few effective immunotherapeutic strategies that generate long-lasting tumor remissions. We previously demonstrated that chronic myelogenous leukemia (CML) patients treated with DLI develop high-titer plasma antibodies specific for CML-associated antigens, the majority of which have been reported to bind nucleic acids These observations led us to predict that circulating antibody-antigen complexes in DLI-responsive patients carry nucleic acids that can engage innate immune sensors. Consistent with this, we report here that post-DLI plasma from 5 CML patients that responded to DLI treatment induced massive upregulation of MIP-1α, IP-10, and IFN-α in normal blood mononuclear cells. Importantly, this was not observed with plasma obtained before DLI and from DLI nonresponders and imatinib-treated patients. This endogenous immunostimulatory activity required nucleic acid and protein for its adjuvant effect and activated antigen-presenting cells through the RNA and DNA sensors TLR8 and TLR9. Presence of the immunoglobulin Fc receptor CD32 enhanced cellular responses, suggesting that immunoglobulins associate with this activity. Finally, a TLR-induced expression signature was detectable in post-DLI but not pre-DLI blood, consistent with an active circulating TLR8/9-stimulating factor. We have therefore demonstrated that effective tumor immunity correlates with the presence of endogenous nucleic acid-immunoglobulin complexes in patient plasma, thus providing a putative mechanism for the induction of potent antigen-specific immunity against malignant cells.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antigen-Antibody Complex / blood*
  • Bone Marrow Transplantation / immunology*
  • Chemokine CCL3 / blood
  • Chemokine CXCL10 / blood
  • Female
  • Graft vs Leukemia Effect / immunology*
  • Humans
  • Immunity, Innate
  • Interferon-alpha / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy*
  • Lymphocyte Transfusion
  • Male
  • Middle Aged
  • Nucleic Acids / immunology
  • Tissue Donors
  • Toll-Like Receptors / immunology*
  • Transplantation, Homologous
  • Up-Regulation
  • Young Adult


  • Antigen-Antibody Complex
  • CCL3 protein, human
  • CXCL10 protein, human
  • Chemokine CCL3
  • Chemokine CXCL10
  • Interferon-alpha
  • Nucleic Acids
  • Toll-Like Receptors