Genetic/Epigenetic Alteration and Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Transforming the Immune Microenvironment with Molecular-Targeted Agents

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) is often diagnosed at an advanced stage, leading to limited treatment options and a poor prognosis. So far, standard systemic therapy for advanced iCCA has been a combination of gemcitabine and cisplatin. However, recent advancements in the understanding of the molecular characteristics of iCCA have opened new possibilities for molecular-targeted therapies and immunotherapy.

Summary: Reportedly, 9-36% of iCCA cases have an inflamed tumor immune microenvironment (TME) based on the immune gene expression signature, which is characterized by the presence of immune cells involved in anti-tumor immune responses. The majority of iCCA cases have a non-inflamed TME with a lack of effector T cells, rendering immune checkpoint inhibitors (ICIs) ineffective in these cases. Interestingly, alterations in the fibroblast growth factor receptor (FGFR2) gene and IDH1/2 gene mutations are often observed in the non-inflamed TME in iCCA. Several mechanisms have been reported for the role of driver mutations on the establishment of TME unique for iCCA. For example, IDH1/2 mutations, which cause an increase in DNA methylation, are associated with the downregulation and hypermethylation of antigen processing and presentation machinery, which may contribute to the establishment of a non-inflamed TME. Therefore, inhibitors targeting IDH1/2 may restore the DNA methylation and expression status of molecules involved in antigen presentation, potentially improving the efficacy of ICIs. FGFR inhibitors may also have the potential to modulate immunosuppressive TME by inhibitingthe suppressor of cytokine signaling 1 and activating the interferon-γ signaling as a consequence of inhibition of the FGFR signal. From this perspective, understanding the molecular characteristics of iCCA, including the TME and driver mutations, is essential for the effective application of ICIs and molecular-targeted therapies.

Key messages: Combination approaches that target both the tumor and immune system hold promise for improving the outcomes of patients with iCCA. Further research and clinical trials are needed to validate these approaches and optimize the treatment strategies for iCCA.

Keywords: Cholangiocarcinoma; Driver mutation; Immune checkpoint inhibitors; Molecular-targeted agents; Tumor immune microenvironment.

Fig. 1.

Comparison of TME classification in iCCA. Four different classifications of the tumor immune microenvironment (TME) in intrahepatic cholangiocarcinoma (iCCA) are presented. The length of each bar represents the reported frequency of each TME subclass. The primary pathways associated with each subclass are depicted at the top of the bar. Inflammation-related pathways are denoted in red, pathways related to mesenchymal response in green, and those linked to cell cycle and tumor growth in black. Unique to typical immune hot and immune cold tumors are the metabolism-related and Wnt/β-catenin signaling pathways, respectively, which are indicated in brown and blue. The predominant cell types infiltrating each subclass of tumors are shown at the bottom of the bar.

Fig. 2.

Role of driver mutation in non-inflamed tumor immune microenvironment (TME): A comparison of HCC and iCCA. a Driver mutation and establishment of non-inflamed TME in HCC. Mutations in the Wnt/β-catenin pathway, including the CTNNB1 mutation, are a well-known driver for hepatocarcinogenesis. The activation of this pathway, reportedly, induces a transcription repressor ATP3 and downregulates CCL4 in melanoma and CCL5 in HCC. Decrease of expression of CCL4/5 may inhibit the recruitment of CD103⁺ dendric cell (DC) and CD8⁺ cytotoxic T cell (CTL). b Driver mutation and establishment of non-inflamed TME in iCCA. Mutations in IDH1/2, and FGFR2 fusions/rearrangements are the characteristic driver mutations for iCCA. Mutant IDH1/2 induces a potent inhibitor of α-KG-dependent DNA demethylases and ten–eleven translocation (TET) enzymes, D-2-hydroxyglutarate (D-2-HG) that catalyze the iterative demethylation of 5-methylcytosine. Therefore, this type of mutation may cause hypermethylation and downregulation of genes including those involved in antigen processing and presentation, contributing to the establishment of a “non-inflamed” in iCCAs. Regarding the FGFR2 alterations, their fusions, and rearrangements induce the constitutive activation of the FGF signaling that lead to the inhibition of the IFN-γ signaling through the induction of SOCS1. Decrease of IFN-γ signaling may also result in the downregulation of antigen processing and presenting machineries. Therefore, it is possible that FGFR2 alterations also contribute to the establishment of a “non-inflamed” phenotype in iCCAs. The red arrows represent activation/induction events, and the gray arrows show inactivation/inhibition events, respectively.