Expression of the large amino acid transporter SLC7A5/LAT1 on immune cells is enhanced in primary sclerosing cholangitis-associated cholangiocarcinoma and correlates with poor prognosis in cholangiocarcinoma

Abstract

Biliary tract cancers (BTC) are rare lethal malignancies arising along the biliary tree. Unfortunately, effective therapeutics are lacking and the prognosis remains dismal even for patients eligible for surgical resection. Therefore, novel therapeutic approaches along with early detection strategies and prognostic markers are urgently needed. Primary sclerosing cholangitis (PSC) is a chronic disease of the bile ducts leading to fibrosis and ultimately cirrhosis. Patients with PSC have a 5-20% lifetime risk of developing BTC; yet the molecular mechanisms that underpin the development of PSC- associated biliary tract cancer (PSC-BTC) have not been fully elucidated. SLC7A5/LAT1, a large amino acid transporter, has been shown to modulate cell growth and proliferation as well as other intracellular processes in solid tumors. In this study, we evaluated SLC7A5 expression in PSC-BTC and in sporadic BTC (sBTC) and its role as a prognostic factor. Analysis of the TGCA cohort showed a significantly higher expression of SLC7A5 in tumor tissue compared with adjacent normal tissue (p = 0.0002) in BTC. In our cohort (comprised of 69 BTC patients including 16 PSC-BTC), SLC7A5/LAT1 expression was observed in both tumor and intratumoral immune cells. A significantly higher percentage of SLC7A5/LAT1 positive intratumoral immune cells was observed in PSC-BTC compared with sBTC (p = 0.004). Multiplex immunofluorescence co-detection by indexing (CODEX) analysis identified CD4⁺ regulatory T lymphocytes and CD68⁺ macrophages as the largest immune cell populations expressing LAT1. SLC7A5/LAT1 expression as well as a higher intratumoral infiltration of SLC7A5/LAT1-positive immune cells (≥2%) were associated with a shorter overall survival in our cohort (LogRank test, p = 0.04 and p = 0.008; respectively). SLC7A5/LAT1 expressing tumors are higher staged tumors (pT3/4 versus pT1/2, p = 0.048). These results underline the potential use of SLC7A5/LAT1 as a prognostic marker in BTC. Furthermore, the higher frequency of SLC7A5/LAT1 positive immune cells in PSC-BTC compared to sBTC may hint at the potential role of SLC7A5/LAT1 in inflammation-driven carcinogenesis.

Keywords: Biliary tract cancer; Cholangiocellular carcinoma; Primary sclerosing cholangitis; SLC7A5.