BAFF and APRIL from activin A-treated DC stimulate T-cells

The members of the TGF-β superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization and survival of different cell types. Although the role of TGF-β1 in inflammation and immunity is well evident, the contribution of other TGF-β family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and up-regulates production of the TNF-α family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DC up-regulate proliferation and survival of T cells expressing the corresponding receptors - BAFF-R and TACI. In vivo, activin A stimulated DC demonstrate a significantly increased ability to induce tumor-specific CTL and inhibit the growth of melanoma and lung carcinoma, which relays on DC-derived BAFF and APRIL since knockdown of the BAFF and APRIL gene expression in activin A-treated DC blocks augmentation of their antitumor potential. Though systemic administration of activin A, BAFF or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and non-malignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pre-treated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction.

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