Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies

Cholangiocarcinoma is characterized by a poor prognosis with limited treatment and management options. Chemotherapy using gemcitabine with cisplatin is the only available first-line therapy for patients with advanced cholangiocarcinoma, although it offers only palliation and yields a median survival of < 1 year. Recently there has been a resurgence of immunotherapy studies focusing on the ability of immunotherapy to inhibit cancer growth by impacting the tumor microenvironment. Based on the TOPAZ-1 trial, the US Food and Drug Administration has approved the combination of durvalumab and gemcitabine with cisplatin as the first-line treatment of cholangiocarcinoma. However, immunotherapy, like immune checkpoint blockade, is less effective in cholangiocarcinoma than in other types of cancer. Although several factors such as the exuberant desmoplastic reaction are responsible for cholangiocarcinoma treatment resistance, existing literature on cholangiocarcinoma cites the inflammatory and immunosuppressive environment as the most common factor. However, mechanisms activating the immunosuppressive tumor microenvironment contributing to cholangiocarcinoma drug resistance are complicated. Therefore, gaining insight into the interplay between immune cells and cholangiocarcinoma cells, as well as the natural development and evolution of the immune tumor microenvironment, would provide targets for therapeutic intervention and improve therapeutic efficacy by developing multimodal and multiagent immunotherapeutic approaches of cholangiocarcinoma to overcome the immunosuppressive tumor microenvironment. In this review, we discuss the role of the inflammatory microenvironment-cholangiocarcinoma crosstalk and reinforce the importance of inflammatory cells in the tumor microenvironment, thereby highlighting the explanatory and therapeutic shortcomings of immunotherapy monotherapy and proposing potentially promising combinational immunotherapeutic strategies.