title: Th1 cytokines are more effective than Th2 cytokines at licensing anti-tumour functions in CD40-activated human macrophages in vitro.
abstract: CD40 agonists are showing activity in early clinical trials in patients with advanced cancer. In animal models, CD40 agonists synergise with T-cell-activating therapies to inhibit tumour growth by driving tumour macrophage repolarisation from an immunosuppressive to a Th1 immunostimulatory, tumouricidal phenotype. We therefore tested the hypothesis that T-cell-derived cytokines license anti-tumour functions in CD40-activated human macrophages. CD40 ligand (CD40L) alone activated macrophages to produce immunosuppressive IL-10, in a similar fashion to bacterial LPS, but failed to promote anti-tumour functions. The Th1 cytokine IFN-γ optimally licensed CD40L-induced macrophage anti-tumour functions, inducing a switch from IL-10 to IL-12p70 production, promoting macrophage-mediated Th1 T-cell skewing and enhancing tumouricidal activity. We found that even the Th2 cytokines IL-4 and IL-13 promoted IL-12p70 production (albeit without inhibiting IL-10 production) and enhanced Th1 T-cell skewing by CD40L-activated macrophages. However, IL-4 and IL-13 did not enhance tumouricidal activity in CD40L-activated macrophages. Thus, while both Th1 and Th2 cytokines biased macrophages to a Th1 immunostimulatory phenotype, only Th1 cytokines promoted tumouricidal activity in CD40L-activated macrophages. The presence of tumour-infiltrating Th1 or Th2 cells might therefore be predictive for patient response to CD40 agonism.
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: Nadia
authors.initials: N
authors.lastname: Luheshi
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.forename: Edmund
authors.initials: E
authors.lastname: Poon
authors.forename: Kimberley
authors.initials: K
authors.lastname: Wiggins
authors.forename: Matthew
authors.initials: M
authors.lastname: McCourt
authors.forename: James
authors.initials: J
authors.lastname: Legg
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D018417:Th1 Cells / Q000276:immunology*; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D016207:Cytokines; D023201:CD40 Ligand
keywords: CD40; Macrophage; Polarisation; Th1/2; Tumour