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Review
. 2023 Sep;79(3):867-875.
doi: 10.1016/j.jhep.2023.05.010. Epub 2023 May 16.

Immunobiology of cholangiocarcinoma

Jennifer L Tomlinson  1 , Juan W Valle  2 , Sumera I Ilyas  3
Affiliations
Review

Immunobiology of cholangiocarcinoma

Jennifer L Tomlinson et al. J Hepatol. 2023 Sep.

Abstract

Recent literature has significantly advanced our knowledge and understanding of the tumour immune microenvironment of cholangiocarcinoma. Detailed characterisation of the immune landscape has defined new patient subtypes. While not utilised in clinical practice yet, these novel classifications will help inform decisions regarding immunotherapeutic approaches. Suppressive immune cells, such as tumour-associated macrophages and myeloid-derived suppressor cells, form a barrier that shields tumour cells from immune surveillance. The presence of this immunosuppressive barrier in combination with a variety of immune escape mechanisms employed by tumour cells leads to poor tumour immunogenicity. Broad strategies to re-equip the immune system include blockade of suppressive immune cell recruitment to priming cytotoxic effector cells against tumour antigens. While immunotherapeutic strategies are gaining traction for the treatment of cholangiocarcinoma, there is a long road of discovery ahead in order to make meaningful contributions to patient therapy and survival.

Keywords: Immunosuppressive myeloid cells; immune evasion; immunogenic; preclinical models.

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Conflict of interest statement

Conflicts of Interest: JWV declares Speakers’ Bureau and honoraria for AstraZeneca and Merck. SII declares consulting for AstraZeneca. JLT declares no conflicts of interest.

Figures

Figure 1 –
Figure 1 –. Genetic and epigenetic alterations employed by CCA to promote immune evasion.
Genetic aberrations frequently identified in the CCA landscape have been linked to mechanisms of immune escape. (A) In IDH1-mutant CCA, oncometabolite (R)-2-hydroxyglutaratesuppresses CD8+ T cell functionality and inactivates TET2, a DNA demethylase, leading to repression of IFNγ response by tumor cells. (B) FGFR2-fusion positive CCAs are associated with reduced PD-L1 expression on tumor cells (C) Increased expression of immune checkpoint molecule, B7-H4, has been associated with loss of function BAP1 mutations resulting in decreased CTL density in the CCA TIME. BAP1, BRCA1 associated protein-1; CCA, cholangiocarcinoma; CTL, cytotoxic T lymphocyte; FGFR2, fibroblast growth factor receptor 2; IDH1, isocitrate dehydrogenase 1; IFNγ, interferon gamma; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand; (R)-2HG, (R)-2-hydroxyglutarate; TET2, ten-eleven translocation-2; TIME, tumor immune microenvironment
Figure 2 –
Figure 2 –. Reengineering the CCA TIME.
Successful application of ICI in CCA relies on reengineering the CCA TIME by promoting the activity of inherent, inflammatory immunogenic elements. CCA, cholangiocarcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; ICI, immune checkpoint inhibition; MDSC, myeloid-derived suppressor cell; NK, natural killer cell; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TIME, tumor immune microenvironment; Treg, regulatory T cell
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