Immunology and immunotherapy of cholangiocarcinoma

Abstract

Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.

Figure 1:

The immune tumour microenvironment in cholangiocarcinoma. This figure provides an overview of the immune microenvironment of cholangiocarcinoma. Different immune cells, either in the tumour surrounding tissue or within the tumour, can have anti-tumour effects or provide an immunosuppressive environment. Tumour infiltrating CD8⁺ T cells and MAITs exert anti-tumour function, and the presence of tertiary lymphoid structures within the tumour is associated with a better outcome. Tumour-associated macrophages, myeloid-derived suppressor cells and tumour-associated neutrophils, along with Foxp3⁺ T_reg cells and cancer-associated fibroblasts, are all associated with worse outcome. Interestingly, tertiary lymphoid structures in the tumour surrounding tissue are also associated with a less favourable outcome. Gram-negative gut-derived bacteria are getting into the liver through the portal vein control intrahepatic MDSC through TLR4 activation on hepatocytes leading to CXCL1 release. MAIT: Mucosal associated invariant T cell; CXCL1: C-X-C Motif Chemokine Ligand 1; TLR4: Toll like receptor 4; TAM: tumour associated macrophage; TAN: tumour associated neutrophil; CAF: cancer associated fibroblast; Treg: T regulatory cell

Figure 2:

Cancer associated fibroblast subtypes and interacting cells in cholangiocarcinoma Cancer-associated fibroblasts can be divided into five different subgroups (inflammatory, myofibroblastic, mesothelial, vascular antigen-presenting and EMT-like). Cancer-associated fibroblasts interact with various immune cells such as MDSC, macrophages, dendritic cells, and T and B cells. They release various cytokines (IL-6, IL-33) and chemokines (CCL2 CXCL2, CXCL12) into the microenvironment. Most CAFs have been shown to promote tumour growth. In contrast, collagen production by CAFs blocks immune cell infiltration and tumour cells, thereby inhibiting tumour growth. CAF: cancer associated fibroblast; EMT: epithelial-mesenchymal transition; CXCL2: : C-X-C Motif Chemokine Ligand 2, CCL2: C-C Motif Chemokine Ligand 2; CXCL12: C-X-C Motif Chemokine Ligand 12; IL-6: interleukin-6; IL-33: interleukin-33.

Figure 3:

Cancer immunotherapy in cholangiocarcinoma. Here are shown different therapeutic approaches, using adoptive T cell therapy, anti-PD1 and/or anti-PDL1, vaccines, bi-specific antibodies, agonistic antibodies and others. The respective target or combination partners are shown outside the circle, and the target cells are shown inside the circle. (BiTE: Bi-specific T-cell engager, CAR-T: Chimeric antigen receptor T cell; TruC: T Cell Receptor Fusion Construct T cell; TIL: tumor infiltrating lymphocytes; EGFR: Epidermal growth factor receptor; MUC-1: mucin 1; CD133: prominin-1, a surface antigen commonly found on cancer stem cells, aCSFR: colony stimulating factor receptor; aLy6G: Lymphocyte antigen 6 commonly found on neutrophils, CD247: CD3zeta chain; FCGR1A: (Fc Gamma Receptor Ia; TRRAP: Transformation/Transcription Domain Associated Protein), TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor)