Key Laboratory of Molecular Oncology of Heilongjiang Province, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang, China; Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang, China.
Key Laboratory of Molecular Oncology of Heilongjiang Province, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang, China; Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang, China; Department of Phase 1 Trials Center, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang, China.
Cytokine. 2023 Sep;169:156271. doi: 10.1016/j.cyto.2023.156271. Epub 2023 Jun 16.
Biliary tract cancer (BTC) is a highly malignant tumor that originates from bile duct epithelium and is categorized into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA) and gallbladder cancer (GBC) according to the anatomic location. Inflammatory cytokines generated by chronic infection led to an inflammatory microenvironment which influences the carcinogenesis of BTC. Interleukin-6 (IL-6), a multifunctional cytokine secreted by kupffer cells, tumor-associated macrophages, cancer-associated fibroblasts (CAFs) and cancer cells, plays a central role in tumorigenesis, angiogenesis, proliferation, and metastasis in BTC. Besides, IL-6 serves as a clinical biomarker for diagnosis, prognosis, and monitoring for BTC. Moreover, preclinical evidence indicates that IL-6 antibodies could sensitize tumor immune checkpoint inhibitors (ICIs) by altering the number of infiltrating immune cells and regulating the expression of immune checkpoints in the tumor microenvironment (TME). Recently, IL-6 has been shown to induce programmed death ligand 1 (PD-L1) expression through the mTOR pathway in iCCA. However, the evidence is insufficient to conclude that IL-6 antibodies could boost the immune responses and potentially overcome the resistance to ICIs for BTC. Here, we systematically review the central role of IL-6 in BTC and summarize the potential mechanisms underlying the improved efficacy of treatments combining IL-6 antibodies with ICIs in tumors. Given this, a future direction is proposed for BTC to increase ICIs sensitivity by blocking IL-6 pathways.
胆管癌（BTC）是一种高度恶性肿瘤，起源于胆管上皮细胞，根据解剖位置可分为肝内胆管癌（iCCA）、肝门部胆管癌（pCCA）、远端胆管癌（dCCA）和胆囊癌（GBC）。慢性感染产生的炎症细胞因子导致炎症微环境影响 BTC 的发生。白细胞介素 6（IL-6）是由枯否细胞、肿瘤相关巨噬细胞、癌相关成纤维细胞（CAFs）和癌细胞分泌的多功能细胞因子，在 BTC 的发生、血管生成、增殖和转移中发挥核心作用。此外，IL-6 可作为 BTC 的临床诊断、预后和监测的生物标志物。此外，临床前证据表明，IL-6 抗体可通过改变浸润免疫细胞的数量和调节肿瘤微环境（TME）中免疫检查点的表达，使肿瘤免疫检查点抑制剂（ICIs）敏感。最近，已经证明 IL-6 通过 mTOR 通路诱导 iCCA 中程序性死亡配体 1（PD-L1）的表达。然而，目前的证据还不足以得出结论，认为 IL-6 抗体可以增强免疫反应，并有可能克服 BTC 对 ICIs 的耐药性。在这里，我们系统地综述了 IL-6 在 BTC 中的核心作用，并总结了 IL-6 抗体与 ICIs 联合治疗提高疗效的潜在机制。基于这一点，提出了未来 BTC 通过阻断 IL-6 途径增加 ICIs 敏感性的方向。
