Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells

Abstract

Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4+ T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications.

Th9 Cells Represent a Unique Subset of CD4+ T Cells Endowed with the Ability to Eradicate Advanced Tumors

“…Our previous study (Lu et al, 2012) revealed a distinct role for Th9 cells in provoking CD8 + CTL-mediated antitumor immunity in an IL-9-dependent manner, which has been confirmed by multiple studies (Kim et al, 2015; Vegran et al, 2014; Zhao et al, 2016b). However, all these studies used early-stage tumor models, which may not represent clinically relevant scenario for ACT.…”

“…Furthermore, subsequent elegant studies also demonstrated the potential for triggering endogenous antitumor Th9 responses in vivo (Kim et al, 2015; Liu et al, 2015; Zhao et al, 2016b), by both an antigen-nonspecific manner via glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein costimulation and by an antigen-specific manner via vaccination. However, the T cell features of Th9 cells beyond IL-9 production and whether these cells can be used to cure late-stage advanced tumors (a scenario more like that seen clinically) have not been explored.…”

TH9 cells in anti-tumor immunity

“…In this setting, the injection of anti-CD8 antibodies nullified the anti-tumor efficacy of T H 9 cell transfer in vivo. The ability of T H 9 cell-derived IL-9 to drive the activation of anti-cancer CD8 T cells was further confirmed recently as illustrated by Zhao et al, who found that immunization of tumor-bearing mice with dectin-1-activated DCs induced potent anti-tumor responses that depended on Th9 cells and the IL-9-dependent induction of anti-cancer CD8 T cells [28]. …”

“…These findings suggest that strategies favoring the generation of T H 9 cell-mediated immune responses may have an important role in the treatment of melanoma in humans. In the light of the latest advances on T H 9 cell anti-tumor properties [28, 32], the use of dendritic cell-based therapeutic cancer vaccines could be considered to generate a T H 9 cell response in cancer patients. Indeed, DC-expressing GITR-L [46] or activated via the dectin-1 signaling pathway [28] may generate a T H 9 cell anti-tumor response that ultimately results in a clinical benefit in cancer patients.…”

Dectin-1-activated dendritic cells: A potent Th9 cell inducer for tumor immunotherapy

“…5,6 We recently used dectin-1 agonist curdlan or Scleroglucan to activate mouse bone marrow (BM)-derived immature DCs (CurDCs or SclDCs) and used these DCs to prime naive CD4 C T cells under Th9-polarizing conditions. 7 We found that dectin-1-activated DCs potently promoted the development of Th9 cells, with upregulated expression of IL-9-and Th9-related transcription factor IRF4, but not other Th cell-related cytokines and transcription factors. Importantly, in the in vivo tests, dectin-1-activated DCs but not regular BMDCs stimulated the powerful production of Th9 cells and IL-9.…”