3rd Immunotherapy of Cancer Conference (ITOC3)
Targeting AFP in hepatocellular cancer
Dr Lisa Butterfield University of Pittsburgh, Pittsburgh, USA
Here at the conference I decided to present some of the work we’re doing in hepatocellular cancer. There we’ve been targeting alpha fetoprotein as a tumour antigen and we’ve found it has immune modulatory function so I presented some of our recent data on those immune modulatory effects of alpha fetoprotein.
What kind of modulation does the antigen have?
We find that in addition to being a target for T-cell responses we also find a number of effects on myeloid cells. We cultured myeloid dendritic cells with alpha fetoprotein, both cord blood derived normal AFP and tumour derived tumour AFP and found some very potent inhibitory effects on the functions of myeloid-derived dendritic cells.
What impact does that have on tumour expression and regulation?
I suspect that it helps co-opt the immune system in favour of the tumour by suppressing the ability of myeloid dendritic cells to present antigen and to promote anti-tumour immunity. One of the effects we see is potent suppression of metabolism of those dendritic cells so that suppresses their ability to activate T-cells, hence promoting tumour and suppressing immunity.
How does this relate to checkpoint inhibitors?
It also suggests that AFP is a potent target that we need to focus on. While it’s not a checkpoint, I think it’s an immune modulatory molecule that is supressing immunity and if we can target it, if we can get rid of the cells that are producing AFP systemically, that it’s floating through the serum, if we can stop that effect then we’ll stop a potent immune suppressive effect of the tumour and that will then enable some of our other efforts at promoting anti-tumour immunity, make those more effective.
What’s next in the pipeline?
We’re following several stories in this area, so the metabolism suppression story is one of those. Another one I presented here is potential modulation of lipid antigen presentation molecules and that may impact NKT cell activation downstream. Another story is chemokine secretion modulation and we find AFP suppresses chemokine secretion by dendritic cells and that may impact and reduce their ability to cross-talk with a wide variety of other cells. Then the last short story that I presented that’s also unpublished is natural killer cell effects. I thought that natural killer cells might be inhibited secondary to the effects on dendritic cells but instead we find direct effects of AFP on NK cells. So we’re investigating the effect of that, it seems to be a short-term skewing effect of the cytokine production by NK cells but an overall loss of viability, particularly with tumour AFP. So effects not just on myeloid derived dendritic cells but also natural killer cells.
What should clinicians be aware of or look out for?
The last five phase III studies looking at small molecule inhibitors have failed for hepatocellular cancer. I think we know much more about the immune modulatory effects of not just AFP but other areas of HCC immunity. So if we can, in this case, perhaps target AFP, and that’s more than half of all hepatocellular cancers, turn on this molecule, so if we can focus on AFP as an immune suppressor in addition to combining other immune modulatory targets I think we might be able to have a greater impact on hepatocellular cancer.