The immune milieu of cholangiocarcinoma: From molecular pathogenesis to precision medicine.

Cholangiocarcinoma (CCA) is a deadly cancer of the biliary epithelium with limited therapeutic options. It is a heterogeneous group of cancer that could develop at any level from the biliary tree and is currently classified into intrahepatic, perihilar and distal based on its anatomical location. With incidence and mortality rates currently increasing, it is now the second most common type of primary liver cancer and represents up to 3% of all gastrointestinal malignancies. High-throughput genomics and epigenomics have greatly increased our understanding of CCA underlying biology, however its pathogenesis remains largely unknown. CCA is characterized by a highly desmoplastic microenvironment containing stromal cells, mainly cancer-associated fibroblasts, infiltrating tumor epithelium. Tumor microenvironment in CCA is a highly dynamic environment that, besides stromal and endothelial cells, encompass also an abundance of immune cells, of both the innate and adaptive immune system (including tumor-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes) and abundant proliferative factors. It is orchestrated by multiple soluble factors and signals, that eventually define a tumor growth-permissive microenvironment. Through complicate interactions with CCA cells, tumor microenvironment profoundly affects the proliferative and invasive abilities of epithelial cancer cells and plays an important role in accelerating neovascularization and preventing apoptosis of neoplastic cells. In this review, we discuss recent developments regarding the characteristics of the tumor microenvironment, the role of each cellular population, and their multiarticulate interaction with the malignant population. Further we discuss innovative treatment approaches, including immunotherapy, and how identification of CCA secreted factors by both the stromal component and immune cell subsets are leading towards a precision medicine in CCA.