TLR ligands efficiently convert tolerogenic CD4‐8‐ DC into immunogenic ones stimulating long‐lasting antitumor immune response

Abstract

Different dendritic cell (DC) subsets play distinct roles in immune responses. CD4−8−DC secreting transforming growth factor (TGF)‐β stimulate CD4+ regulatory T type 1 (Tr1) cell responses leading to antitumor immune tolerance. CD4−8−DC could be converted into inducing Th1 rather Tr1 by being cultured for another 16–24 hrs and pulsed with 1 mg/ml OVA protein. In this study we investigate whether TLR ligands, agonist anti‐CD40 and their combinations could more efficiently convert CD4−8−DC to induce Th1 response. We found that CpG, LPS and anti‐CD40 alone or CpG+anti‐CD40, but not LPS+anti‐CD40 stimulate those DCs to express similar higher level of CD40, CD54, CD80, CD86 and I‐Ab after 8hrs culture than newly isolated DCs; Among the above groups, CpG group showed the strongest capacity of stimulating the proliferation of OT1 CD8 and OTII CD4 T cells and induced 100% animal protection from tumor challenge with highest OVAI specific CTL ratio and in vivo cytotoxicity; LPS+anti‐CD40 group was the weakest in every above aspect and could not provide any animal protection. Taken together, our findings indicate that CpG 8 hrs treatment could convert tolerogenic DC into immunogenic ones provoking strong antitumor immunity; and TLR ligands plus anti‐CD40 combination should be carefully tested before using as adjuvant for DC maturation. Thus our results might have great impact on designing the future tumor vaccine.