Work

Spatial mapping of the HCC landscape identifies unique intratumoral perivascular-immune neighborhoods

Year: 2024

Type: article

Abstract: Background & Aims Hepatocellular carcinoma (HCC) develops in the context of chronic inflammation, however, the opposing roles the immune system plays in both the development and control of tumours is not fully understood. Mapping immune cell interactions across the distinct tissue regions could provide greater insight into the role individual immune populations have within tumours. Methods A 39-parameter imaging mass cytometry panel was optimised with markers targeting immune cells, stromal cells, endothelial cells, hepatocytes, and tumour cells. We mapped the immune landscape of tumour, invasive margin, and adjacent non-tumour regions across sixteen resected tumours comprising of 144 regions of interest. X-shift clustering and manual gating were used to characterise cell subsets, and Spectre quantified the spatial environment to identify cellular neighbourhoods. Ligand-receptor communication was quantified on two single-cell RNA-sequencing datasets and one spatial transcriptomic dataset. Results We show immune cell densities remain largely consistent across these three regions, except for subsets of monocyte-derived macrophages which are enriched within the tumours. Mapping cellular interactions across these regions in an unbiased manner identifies immune neighbourhoods comprised of tissue-resident T cells, dendritic cells, and various macrophage populations around perivascular spaces. Importantly, we identify multiple immune cells within these neighbourhoods interacting with VEGFA + perivascular macrophages. VEGFA was further identified as a ligand for communication between perivascular macrophages and CD34 + endothelial cells. Conclusions Immune cell neighbourhood interactions, but not cell densities, differ between intratumoural and adjacent non-tumour regions in HCC. Unique intratumoural immune neighbourhoods around the perivascular space points to an altered landscape within tumours. Enrichment of VEGFA + perivascular macrophages within these tumours could play a key role in angiogenesis and vascular permeability. Impact and Implications We investigated the landscape of immune cells within liver cancer. A unique perivascular neighbourhood of immune cells was identified. This is important as the interaction of immune cells and the vasculature in liver cancer is a therapeutic target of current systemic therapy. The characterisation in detail of this neighbourhood may potentially identify additional targets for future therapies. Highlights Imaging mass cytometry using 39 markers was used to map immune-infiltrating cells in hepatocellular carcinoma (HCC) Perivascular macrophages (PVM) were seen to form unique intratumoural neighbourhoods with immune cells PVM were identified as VEGFA + within HCC tumours

Source: Hepatology Communications

DOI: 10.1097/hc9.0000000000000540