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.

Keywords: CD40; Macrophage; Polarisation; Th1/2; Tumour.