The aim of the project is to study the crosstalk between immune cells and the extracellular matrix (ECM) in primary (HCC) and secondary (colon cancer metastasis) liver cancer using patient-derived cells and ECM extracts. The final goal is to understand how the extracellular compartment of the tumour microenvironment can modulate immune cell activity and phenotypes.
The interaction of tumour microenvironment (TME) with cancer cells is closely involved with tumour development, progression and drug resistance. The TME is a complex network composed of multiple non-malignant cells including cancer associated fibroblasts (CAFs), endothelial cells, immune and inflammatory cells and the ECM. The ECM is a dynamic web of molecules that provides structural support and biochemical cues and is fundamental in different tissue processes.
It is well established that liver cancer is associated with profound remodelling of the liver ECM, which becomes stiffer and modulates cell behaviour, tumour progression, metastatic dissemination and immune cell evasion and function. While it is known that the ECM has immunomodulatory properties, the impact of tumour-specific ECM proteins on anti-tumour immune responses is unknown.
Immunotherapy and in particular checkpoint receptor inhibition (CRI) is a promising therapeutic avenue in liver cancer to rescue exhausted and dysfunctional immune cells and restore anti-tumour immunity. However, in HCC response rate is only 20% and many patients are resistant to CRI or become refractory after an initial response. The role of the ECM in response or resistance to CRI in liver cancers in unknown.
Our team has been addressing these issues by combining studies of liver immunology and checkpoint receptors, and the knowledge and technologies in matrix biology of Dr Urbani’s group (Liver Regeneration and Tissue Engineering).
With this project, we aim to determine the immunomodulatory properties of specific cancer ECM proteins in HCC and other liver cancers and their potential role in orchestrating tumour-specific immunity and response to immunotherapy. The project originates from ground-breaking preliminary data collected by the team, which included data from co-cultures of circulating and tissue infiltrating human immune cells and with different ECM-extracts obtained with decellularisation of tissue samples.
These co-cultures will be performed with a larger cohort of samples and pathways identified will be further investigated in co-culture experiments of immune cells with in vitro hepatic stellate cells- or CAF-derived matrix obtained in vitro with established protocols, to better understand mechanisms of interaction of immune cells with the remodelled tumour ECM.
Different techniques will be used to characterise the immune cell response to the different patient derived ECMs and then correlate the findings with in vivo/clinical data. Techniques will include: FACS, Luminex, T cell proliferation assay, proteomics, spatial transcriptomics and proteomics, etc.
In conclusion, we aim to show how individual components of the remodelled ECM in liver cancer can impede anti-tumour immunity and, by identifying therapeutic targets, how these effects might be mitigated. This project could provide a precious body of knowledge about how the ECM shields the tumour from the immune system and may control local response to CRI and could open new therapeutic avenues in treating liver cancer.