Attenuating Regulatory T Cell Induction by TLR Agonists through Inhibition of p38 MAPK Signaling in Dendritic Cells Enhances Their Efficacy as Vaccine Adjuvants and Cancer Immunotherapeutics

Abstract

TLR ligands are potent adjuvants and promote Th1 responses to coadministered Ags by inducing innate IL-12 production. We found that TLR ligands also promote the induction of IL-10-secreting regulatory T (Treg) cells through p38 MAPK-induced IL-10 production by dendritic cells (DC). Inhibition of p38 suppressed TLR-induced IL-10 and PGE2 and enhanced IL-12 production in DC. Incubation of Ag-pulsed CpG-stimulated DC with a p38 inhibitor suppressed their ability to generate Treg cells, while enhancing induction of Th1 cells. In addition, inhibition of p38 enhanced the antitumor therapeutic efficacy of DC pulsed with Ag and CpG and this was associated with an enhanced frequency of IFN-γ-secreting T cells and a reduction of Foxp3+ Treg cells infiltrating the tumors. Furthermore, addition of a p38 inhibitor to a pertussis vaccine formulated with CpG enhanced its protective efficacy in a murine respiratory challenge model. These data demonstrate that the adjuvant activity of TLR agonists is compromised by coinduction of Treg cells, but this can be overcome by inhibiting p38 signaling in DC. Our findings suggest that p38 is an important therapeutic target and provides a mechanism to enhance the efficacy of TLR agonists as vaccine adjuvants and cancer immunotherapeutics.

Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination

“…In this context, IL-10 is a cytokine whose activity in antitumor immune responses is controversial. Although some authors report an immunosuppressive effect, 10,33 in other cases it has been demonstrated to possess a beneficial role. 18,19 Since these effects have been reported in different settings, in the present study we focused on the role of IL-10 during therapeutic vaccination.…”

“…9 Besides this scenario, some therapies, such as vaccines containing immunostimulatory adjuvants, have been shown to induce the production of IL-10 by APC, resulting in diminished Th1 immune responses. 10,11 Indeed, although vaccines based on combinations of selected tumor antigens with adjuvants inducing optimal APC activation may lead to proper antitumor T cell priming, [12][13][14] this may be accompanied by activation of regulatory feed-back mechanisms, such as IL-10 production. 15 This has led to the hypothesis that combination of these immune-activating strategies with blockade of IL-10 may have a higher immunotherapeutic effect.…”

Targeted inhibition of IL‐10‐secreting CD25− Treg via p38 MAPK suppression in cancer immunotherapy

“…We now suspect that the dominant p38 activation in response to other MAPK (ERK and JNK) in in vivo Ag-induced iTreg is related to both the suppressor function via IL-10 production and the anergic state via cell cycle arrest and p27 expression and not via IL-10 [14]. Recent studies have indicated that p38 activation is required for TGF-b-induced in vitro conversion to iTreg [23,24] and is involved in IL-10 production via innate TLR2 signaling of HSP60 in iTreg [25] or in the induction to iTreg through tDC treated with CpG [26]. We suspect that p38-dependent IL-10 production is mediated by TAB1.…”

TLR-dependent T cell activation in autoimmunity

“…Activation of the interferon regulatory factor (IRF) pathways mediate IL-12p35 and type I interferon (IFN) production, whereas active extracellular signal-regulated kinase (ERK) and p38 MAP kinases are required for IL-23p19 and IL-10 production respectively 5,[12][13] (FIG. 1).…”