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

IF 2.7 2区医学 Q2 PATHOLOGY

Human pathology Pub Date : 2024-10-13 DOI:10.1016/j.humpath.2024.105670

Vittorio Branchi , Racha Hosni , Lukas Kiwitz , Susanna Ng , Gemma van der Voort , Neila Bambi , Eileen Kleinfelder , Laura K. Esser , Leona Dold , Bettina Langhans , Maria A. Gonzalez-Carmona , Saskia Ting , Glen Kristiansen , Jörg C. Kalff , Kevin Thurley , Michael Hölzel , Hanno Matthaei , Marieta I. Toma

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引用次数: 0

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.

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原发性硬化性胆管炎相关胆管癌的免疫细胞中大氨基酸转运体 SLC7A5/LAT1 的表达增强，并与胆管癌的不良预后有关

胆道癌（BTC）是沿胆道树发生的罕见致命恶性肿瘤。遗憾的是，目前缺乏有效的治疗方法，即使是符合手术切除条件的患者，其预后也仍然不容乐观。因此，迫切需要新的治疗方法、早期检测策略和预后标志物。原发性硬化性胆管炎（PSC）是一种导致胆管纤维化并最终导致肝硬化的慢性疾病。PSC患者一生中患胆管癌的风险为5%-20%；然而，PSC相关胆管癌（PSC-BTC）发病的分子机制尚未完全阐明。SLC7A5/LAT1是一种大型氨基酸转运体，已被证明可调节细胞生长和增殖以及实体瘤的其他细胞内过程。在这项研究中，我们评估了 SLC7A5 在 PSC-BTC 和散发性 BTC（sBTC）中的表达及其作为预后因素的作用。对 TGCA 队列的分析表明，在 BTC 中，肿瘤组织中 SLC7A5 的表达明显高于邻近的正常组织（p = 0.0002）。在我们的队列（由 69 名 BTC 患者组成，包括 16 名 PSC-BTC）中，肿瘤和瘤内免疫细胞中都观察到了 SLC7A5/LAT1 的表达。与 sBTC 相比，PSC-BTC 中 SLC7A5/LAT1 阳性的瘤内免疫细胞比例明显更高（p = 0.004）。在我们的队列中，SLC7A5/LAT1的表达以及SLC7A5/LAT1阳性免疫细胞较高的瘤内浸润（≥2%）与较短的总生存期相关（LogRank检验，分别为p = 0.04和p = 0.008；）。SLC7A5/LAT1 表达的肿瘤分期更高（pT3/4 与 pT1/2，p = 0.048）。此外，与sBTC相比，PSC-BTC中SLC7A5/LAT1阳性免疫细胞的频率更高，这可能暗示了SLC7A5/LAT1在炎症驱动的癌变中的潜在作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human pathology 医学-病理学

CiteScore

5.30

自引率

6.10%

发文量

206

审稿时长

21 days

期刊介绍： Human Pathology is designed to bring information of clinicopathologic significance to human disease to the laboratory and clinical physician. It presents information drawn from morphologic and clinical laboratory studies with direct relevance to the understanding of human diseases. Papers published concern morphologic and clinicopathologic observations, reviews of diseases, analyses of problems in pathology, significant collections of case material and advances in concepts or techniques of value in the analysis and diagnosis of disease. Theoretical and experimental pathology and molecular biology pertinent to human disease are included. This critical journal is well illustrated with exceptional reproductions of photomicrographs and microscopic anatomy.