P62 Prognostic value and potential immunoregulatory role of SCARF1 in hepatocellular carcinoma

The immune microenvironment plays a key role in determining the pathogenesis and progression of hepatocellular carcinoma (HCC). Some immune cell subsets promote tumour growth whilst others drive anti-tumour responses. Elucidating the mechanisms by which distinct immune subsets are recruited to the HCC microenvironment could lead to novel immunotherapies. Immune cell recruitment follows a generalized stepwise process, termed the adhesion cascade. We have previously shown that liver endothelial cells express a number of atypical adhesion molecules, such as scavenger receptors, which contribute to immune cell selectivity within the adhesion cascade and thus shape the hepatic immune microenvironment. Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4+ T cells to liver sinusoidal endothelial cells during chronic liver disease; however, its contribution to the pathophysiology of hepatocellular carcinoma (HCC) is currently unknown. In this study, we investigated the expression of SCARF1 in HCC tumours and explored its potential role in the recruitment of CD4+ T cells to the tumour microenvironment. Using TGCA (The Cancer Genome Atlas) RNA-sequencing datasets, we identified the downregulation of SCARF1 expression in HCC tumours, compared to non-tumourous tissues, and validated these findings with immunohistochemical staining of HCC resection specimens. We next explored the relationship of SCARF1 expression with tumour progression and found that a loss of SCARF1 expression was associated with aggressive tumour biology. Following this, we evaluated the prognostic value of SCARF1 expression in HCC tumours and demonstrated that high SCARF1 expression in HCC tumour tissues correlates with a better overall survival, disease-free survival and progression-free survival. Next, via a combination of TGCA data analysis and dual colour immunofluorescent staining, we confirmed that SCARF1 within HCC was largely associated with tumour endothelial cells. We then undertook flow-based recruitment assays under physiological levels of shear stress with primary liver-derived endothelial cells and purified CD4+ T cell subsets. We demonstrated that SCARF1 mediated a role in the specific recruitment of effector CD4+ T cells (CD4+CD25-) across liver endothelium, rather than immunosuppressive regulatory T cell subsets. Our data suggests that endothelial SCARF1 expression in tumour biopsies may provide critical prognostic information and may potentially help in selecting HCC patients for immunotherapy trials. Regulating SCARF1 levels could itself be a novel immunotherapeutic approach that re-programmes the microenvironment of HCC tumours by promoting effector CD4+ T cell infiltration.