Abstract
We recently discovered that dectin-1-activated dendritic cells (DCs) drive potent T helper (Th) 9 cell responses and antitumor immunity. However, the underlying mechanisms need to be further defined. The cytokine microenvironment is critical for Th cell differentiation. Here, we show that dectin-1 activation enhances interleukin (IL)-33 expression in DCs. We found that blocking IL-33/ST2 inhibits dectin-1-activated DC-induced Th9 cell differentiation. More importantly, the addition of IL-33 further promotes Th9 cell priming and antitumor efficacy induced by dectin-1-activated DCs. Mechanistically, in addition to the promotion of Th9 and Th1 cells, dectin-1-activated DCs combined with IL-33 abolish the activity of IL-33 in the induction of regulatory T cells. Furthermore, the combined treatment of dectin-1-activated DCs and IL-33 increases the frequencies of CD4+ T cells by fostering their proliferation and inhibiting their exhaustive differentiation. Thus, our results demonstrate the important role of IL-33 in dectin-1-activated DC-induced Th9 cell differentiation and antitumor efficacy, and suggest that the combination of dectin-1-activated DCs and IL-33 may present a new effective modality of DC-based vaccines in tumor immunotherapy.
Highlights
Dendritic cell (DC) vaccines offer a great promise for tumor therapy; clinical trials of dendritic cells (DCs)-based tumor therapy have shown only limited clinical benefits [1, 2]
SclDCs had higher expression of IL-33 than BMDCs (Figures 1B–D). These results indicated that dectin-1 agonists drove IL-33 expression in DCs
We recently reported that dectin-1-activated DCs promote Th9 cell differentiation and trigger potent therapeutic effects against established tumors, better than regular BMDCs [12, 13]
Summary
Dendritic cell (DC) vaccines offer a great promise for tumor therapy; clinical trials of DC-based tumor therapy have shown only limited clinical benefits [1, 2]. DCs exert their antitumor effects mainly through the induction of antitumor effector T cells [3, 4]. Naive CD4+ T cells can differentiate into various T helper (Th) cell subsets with different cytokine-production profiles and effector functions [5]. Th9 cells are a new Th cell subset that produces interleukin 9 (IL-9) [6, 7]. We and others recently found that tumor-specific Th9 cells induce potent antitumor efficacy in mouse tumor models, better than other Th cells [10,11,12]. Th9 cells may exert their antitumor effects
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