title: HLA-DR+ immature cells exhibit reduced antigen-presenting cell function but respond to CD40 stimulation.
abstract: Dendritic cells (DC) have been implicated in the defective function of the immune system during cancer progression. We have demonstrated that patients with cancer have fewer myeloid (CD11c+) and plasmacytoid (CD123(hi)) DC and a concurrent accumulation of CD11c(-)CD123- immature cells expressing HLA-DR (DR(+)IC). Notably, DR(+)IC from cancer patients have a reduced capacity to stimulate allogeneic T-cells. DR(+)IC are also present in healthy donors, albeit in smaller numbers. In this study, we assessed whether DR(+)IC could have an impact on the immune response by comparing their function with DC counterparts. For this purpose, DR(+)IC and DC were purified and tested in the presentation of antigens through major histocompatibility complex (MHC) II and MHC-I molecules. DR(+)IC were less efficient than DC at presenting antigens to T-cells. DR(+)IC induced a limited activation of T-cells, eliciting poor T-helper (Th) 1 and preferentially inducing Th2-biased responses. Importantly, despite DR(+)IC's poor responsiveness to inflammatory factors, in samples from healthy volunteers and breast cancer patients, CD40 ligation induced phenotypic maturation and interleukin 12 secretion, in turn generating more efficient T-cell responses. These data underscore the importance of inefficient antigen presentation as a mechanism for tumor evasion and suggest an approach to improve the efficacy of DC-based immunotherapy for cancer.
authors.affiliation: Dendritic Cell and Cancer Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pinzon-Charry
authors.forename: Tammy
authors.initials: T
authors.lastname: Maxwell
authors.forename: Sandro
authors.initials: S
authors.lastname: Prato
authors.forename: Colin
authors.initials: C
authors.lastname: Furnival
authors.forename: Chris
authors.initials: C
authors.lastname: Schmidt
authors.forename: José Alejandro
authors.initials: JA
authors.lastname: López
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000276:immunology / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation / Q000502:physiology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000494:pharmacology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D006684:HLA-DR Antigens; D007371:Interferon-gamma