Zimmer Christine L, Filipovic Iva, Cornillet Martin, O'Rourke Colm J, Berglin Lena, Jansson Hannes, Sun Dan, Strauss Otto, Hertwig Laura, Johansson Helene, von Seth Erik, Sparrelid Ernesto, Dias Joana, Glaumann Hans, Melum Espen, Ellis Ewa C, Sandberg Johan K, Andersen Jesper B, Bergquist Annika, Björkström Niklas K
Center for Infectious Medicine, Department of Medicine HuddingeKarolinska Institutet, Karolinska University HospitalStockholmSweden.
Biotech Research and Innovation Centre (BRIC)Department of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark.
Hepatology. 2022 May;75(5):1154-1168. doi: 10.1002/hep.32222. Epub 2021 Dec 22.
Cholangiocarcinoma (CCA) is a malignancy arising from biliary epithelial cells of intra- and extrahepatic bile ducts with dismal prognosis and few nonsurgical treatments available. Despite recent success in the immunotherapy-based treatment of many tumor types, this has not been successfully translated to CCA. Mucosal-associated invariant T (MAIT) cells are cytotoxic innate-like T cells highly enriched in the human liver, where they are located in close proximity to the biliary epithelium. Here, we aimed to comprehensively characterize MAIT cells in intrahepatic (iCCA) and perihilar CCA (pCCA).
Liver tissue from patients with CCA was used to study immune cells, including MAIT cells, in tumor-affected and surrounding tissue by immunohistochemistry, RNA-sequencing, and multicolor flow cytometry. The iCCA and pCCA tumor microenvironment was characterized by the presence of both cytotoxic T cells and high numbers of regulatory T cells. In contrast, MAIT cells were heterogenously lost from tumors compared to the surrounding liver tissue. This loss possibly occurred in response to increased bacterial burden within tumors. The residual intratumoral MAIT cell population exhibited phenotypic and transcriptomic alterations, but a preserved receptor repertoire for interaction with tumor cells. Finally, the high presence of MAIT cells in livers of iCCA patients predicted long-term survival in two independent cohorts and was associated with a favorable antitumor immune signature.
MAIT cell tumor infiltration associates with favorable immunological fitness and predicts survival in CCA.
胆管癌（CCA）是一种起源于肝内和肝外胆管上皮细胞的恶性肿瘤，预后不佳且可用的非手术治疗方法很少。尽管近年来基于免疫疗法在许多肿瘤类型的治疗中取得了成功，但这尚未成功应用于CCA。黏膜相关恒定T（MAIT）细胞是细胞毒性固有样T细胞，在人类肝脏中高度富集，它们紧邻胆管上皮。在此，我们旨在全面表征肝内胆管癌（iCCA）和肝门周围胆管癌（pCCA）中的MAIT细胞。
利用CCA患者的肝组织，通过免疫组织化学、RNA测序和多色流式细胞术研究肿瘤受累组织和周围组织中的免疫细胞，包括MAIT细胞。iCCA和pCCA肿瘤微环境的特征是存在细胞毒性T细胞和大量调节性T细胞。相比之下，与周围肝组织相比，肿瘤中的MAIT细胞异质性缺失。这种缺失可能是对肿瘤内细菌负荷增加的反应。肿瘤内残留的MAIT细胞群体表现出表型和转录组改变，但保留了与肿瘤细胞相互作用的受体库。最后，iCCA患者肝脏中MAIT细胞的高存在预示着两个独立队列中的长期生存，并与良好的抗肿瘤免疫特征相关。
MAIT细胞肿瘤浸润与良好的免疫适应性相关，并可预测CCA患者的生存。
