Cholangiocarcinoma - novel biological insights and therapeutic strategies

Abstract

In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.

Fig. 1 |. Therapeutically re-engineering the TIME of CCA to reduce tumour burden.

The cholangiocarcinoma (CCA) tumour immune microenvironment (TIME) is poorly immunogenic with an abundance of immunosuppressive cell types such as myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T (T_reg) cells that foster tumour growth and progression. Immunotherapeutic strategies that have been investigated in preclinical studies using mouse models include neutralization of granulocyte–macrophage colony-stimulating factor (GMCSF), liver X-receptor (LXR) agonism to inhibit MDSCs combined with macrophage inhibition using anti-colony-stimulating factor 1 receptor (CSF1R) antibodies and immune-checkpoint inhibitors (ICIs), as well as the combination of ICIs with CD40 agonism or MEK inhibition with trametinib. These immunotherapeutic strategies have the potential to re-engineer the CCA TIME to an immunogenic one that is less favourable to the tumour. NK, natural killer.

Fig. 2 |. Different shades of CAF heterogeneity in CCA.

Cholangiocarcinoma (CCA) is a highly desmoplastic tumour type characterized by a rich stroma with an abundance of fibroblasts and their molecular products. These cancer-associated fibroblasts (CAFs) are heterogeneous in several aspects including their cell of origin, mainly arising from hepatic stellate cells (HSCs) and portal fibroblasts (PFs). Moreover, transcriptomically diverse CAF subtypes have been described to coexist in the same tumour and include vascular CAFs (vCAF), inflammatory CAFs (iCAF), myofibroblastic CAFs (myCAF) and antigen-presenting CAFs (apCAF). CAF heterogeneity is also reflected in their functionality, with evidence for subtypes with tumour-promoting and/or tumour-restricting activities. Furthermore, diverse CAF subtypes are likely to interact differentially with tumour cells and other cells in the tumour microenvironment (TME) during tumorigenesis.