title: Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid-immunoglobulin complexes in humans.
abstract: 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.
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Ann X
authors.initials: AX
authors.lastname: Cai
authors.forename: Mark
authors.initials: M
authors.lastname: Lee
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Christine M
authors.initials: CM
authors.lastname: Canning
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000936:Antigen-Antibody Complex / Q000097:blood*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D054405:Chemokine CCL3 / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood; D005260:Female; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000097:blood; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D009696:Nucleic Acids / Q000276:immunology; D014019:Tissue Donors; D051193:Toll-Like Receptors / Q000276:immunology*; D014184:Transplantation, Homologous; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000936:Antigen-Antibody Complex; C515429:CCL3 protein, human; C114753:CXCL10 protein, human; D054405:Chemokine CCL3; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D009696:Nucleic Acids; D051193:Toll-Like Receptors