Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies

Abstract

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.

Octamer-binding transcription factor 4-positive circulating tumor cell predicts worse treatment response and survival in advanced cholangiocarcinoma patients who receive immune checkpoint inhibitors treatment

“…ICI treatment boosts the host immune system, attacks tumors, and inhibits tumor growth, and is currently a new option for treating many malignant tumors, including CCA [ 40 ]. However, not all advanced CCA patients respond well to ICI treatment, thus predicting the efficacy of ICI treatment in advanced CCA patients is important [ 16 , 17 ]. Interestingly, there is a general negative correlation between cancer stemness and anticancer immunity, thus cancer stemness might affect the efficacy of ICI treatment in cancer patients [ 41 , 42 ].…”

“…Especially, immune checkpoint inhibitors (ICI) treatment is deemed to enhance antitumor immune response and thus improve patients’ survival outcomes [ 13 – 15 ]. However, not all advanced CCA patients respond well to ICI treatment [ 16 , 17 ]. Thus, predicting the efficacy of ICI treatment in advanced CCA patients is a noteworthy issue.…”

Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes

“…The intricate nature of the immune microenvironment in CCA contributes to inconsistent responses to anti-tumor treatments observed in patients [ 17 ]. A deeper understanding of the heterogeneity of immune infiltrates within CCA tumors can help develop personalized anti-tumor immunotherapies.…”

“…The findings regarding the efficacy of the treatment combining durvalumab with first-line chemotherapy regimens in advanced CCA are promising. They indicate that in the imminent future durvalumab in combination with GemCis may become a novel first-line standard therapy for CCA [16]. This review focuses primarily on the influence of infiltrating T lymphocytes on CCA progression.…”

Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies

“…The CCA stroma comprises extracellular matrix proteins, endothelial and mesenchymal cells, as well as cancer-associated fibroblasts (CAFs) [142]. Once recruited and activated by CCA cells, the stromal compartment in turn releases a wide variety of paracrine signals, including chemokines, growth factors, and proteases, to shape the tumor microenvironment [143]. Especially, CAFs have been shown to foster CCA proliferation and drug resistance by releasing signaling molecules and ECM proteins, as well as by recruiting myeloid-derived suppressor cells via IL-6 signaling [144,145].…”