Abstract
There is growing interest in myeloid (my) dendritic cells (DC) as an alternative to monocyte-derived DC (moDC) for immunotherapy.
However, in contrast to moDC, little is known regarding the effect of malignancy on the function, abundance or use
of intracellular signaling pathways in myDC. Understanding the molecular detail of circulating myDC is therefore important for
future use in advanced cancer. Advanced cancer patients had similar numbers of circulating myDC to cancer-free patients and
healthy individuals, and secreted similar levels of IL-1b, IL-6, IL-10, IL-12 and IL-23. However, myDC from some patients failed
to secrete the Th1-cytokine IL-12. Surprisingly, inhibiting p38 (p38i) signaling (using BIRB0796 or SB203580) markedly
increased IL-12 secretion by myDC. This is in complete contrast to what is established for moDC where inhibiting p38 ablates
IL-12. Interestingly, this was specific to IL-12, since IL-10 was suppressed by p38i in both DC types. The opposing effect of
p38i on IL-12 was evident at the transcriptional level and in both DC types was mediated through the p38-MK2 pathway but
did not involve differential phosphorylation of the distal Rsk kinase. Importantly, where patient myDC did not secrete IL-12 (or
after treatment with suppressive melanoma lysate), p38i restored IL-12 to normal levels. In contrast to p38, inhibiting the
other MAPK pathways had similar consequences in both DC types. We show for the first time the differential use of a major
intracellular signaling pathway by myDC. Importantly, there are sufficient circulating myDC in advanced cancer patients to consider
development of adoptive immunotherapy.
However, in contrast to moDC, little is known regarding the effect of malignancy on the function, abundance or use
of intracellular signaling pathways in myDC. Understanding the molecular detail of circulating myDC is therefore important for
future use in advanced cancer. Advanced cancer patients had similar numbers of circulating myDC to cancer-free patients and
healthy individuals, and secreted similar levels of IL-1b, IL-6, IL-10, IL-12 and IL-23. However, myDC from some patients failed
to secrete the Th1-cytokine IL-12. Surprisingly, inhibiting p38 (p38i) signaling (using BIRB0796 or SB203580) markedly
increased IL-12 secretion by myDC. This is in complete contrast to what is established for moDC where inhibiting p38 ablates
IL-12. Interestingly, this was specific to IL-12, since IL-10 was suppressed by p38i in both DC types. The opposing effect of
p38i on IL-12 was evident at the transcriptional level and in both DC types was mediated through the p38-MK2 pathway but
did not involve differential phosphorylation of the distal Rsk kinase. Importantly, where patient myDC did not secrete IL-12 (or
after treatment with suppressive melanoma lysate), p38i restored IL-12 to normal levels. In contrast to p38, inhibiting the
other MAPK pathways had similar consequences in both DC types. We show for the first time the differential use of a major
intracellular signaling pathway by myDC. Importantly, there are sufficient circulating myDC in advanced cancer patients to consider
development of adoptive immunotherapy.
| Original language | English |
|---|---|
| Pages (from-to) | 575-586 |
| Journal | International Journal of Cancer |
| Volume | 134 |
| DOIs | |
| Publication status | Published - 13 Sept 2013 |