Potential role of BMP-9 in the regulation of PD-L1/PD1-mediated immune evasion of HCC cells

Blockade of immune-regulatory receptors, such as programmed cell death protein-1 (PD-1), in order to overcome immune evasion mechanisms is by now implemented into the standard therapies of an increasing number of tumour entities. Such immunotherapy fails to be responsive in a major proportion of patients with HCC. Several possible reasons for unresponsiveness are under investigation, including the predictive level of expression of PD-L1/PD1. We therefore investigated if the liver-derived cytokine bone morphogenetic protein (BMP)-9 plays a role in regulating PD-L1/PD1 expression in tumour cells as well as macrophages.

We have recently shown that LPS-mediated secretion of IL-6 from LSEC leads to enhanced expression of BMP-9 in liver myofibroblasts. BMP-9 in turn enhances IL-6 expression in macrophages, demonstrating a cross-relationship between IL-6 and BMP-9 in liver (Gaitantzi et al., Cells 2020).

In HCC patients high IL-6 correlated with high PD-L1 (Chan et al., JCI 2019). We now found that BMP-9 induces expression of PD-L1 and IL-6R on hepatocellular carcinoma cells (HLE). In blood-derived macrophages BMP-9 induced expression of Pdcd1 (PD1). By analyzing publicly available patient data we found that the presence of the BMP-9 receptor, ALK1, positively correlates with protein levels of PD-L1 in HCC, implying that BMP-9 signalling might be relevant in this context.

We also found that HLE cells express high levels of c-Met (HGF-receptor) and that similar to PD-L1, also cMet protein levels are positively correlated with ALK1 in patient (HCC) samples. Together with our observation that BMP-9 upregulates expression of HGF in hepatocytes, data showing that HGF signalling regulates PD-L1 expression in HCC cells (Li et al., Gastroenterology 2019) and the finding that BMP-9 and HGF signalling seem to potentiate each other (at least in liver progenitor cells: Addante et al., Cells 2020), we hypothesize that the BMP-9/HGF axis may also be relevant in the regulation of PD-L1/PD1 mediated immune evasion of HCC cells.

In summary our data point to an important role of BMP-9 in modulating the effects of HGF and IL-6 on the regulation of immune-checkpoint proteins in HCC. Thereby targeting BMP-9 might be an interesting future approach for immuno-therapy of HCC patients.

Publication History

Article published online:
08 September 2020