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Cadamuro et al. Hepatoma Res 2022;8:11 Hepatoma Research
DOI: 10.20517/2394-5079.2021.140

Review Open Access

Tumor microenvironment and immunology of

cholangiocarcinoma

1
2
1
Massimiliano Cadamuro , Luca Fabris , Xuchen Zhang , Mario Strazzabosco 3
1
Department of Molecular Medicine (DMM), University of Padua, Padua 35131, Italy.
2
Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
3
Liver Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
Correspondence to: Prof. Mario Strazzabosco, Liver Center, Department of Internal Medicine, Yale School of Medicine, 333
Cedar Street, LMP 1080, New Haven, CT 06520, USA. E-mail: mario.strazzabosco@yale.edu
How to cite this article: Cadamuro M, Fabris L, Zhang X, Strazzabosco M. Tumor microenvironment and immunology of
cholangiocarcinoma. Hepatoma Res 2022;8:11. https://dx.doi.org/10.20517/2394-5079.2021.140
Received: 9 Nov 2021 First Decision: 24 Jan 2022 Revised: 27 Jan 2022 Accepted: 8 Feb 2022 Published: 11 Mar 2022

Academic Editor: Gabriele Missale Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
Cholangiocarcinoma (CCA), an aggressive tumor originating from both intra- and extra-hepatic biliary cells,
represents an unmet need in liver oncology, as treatment remains largely unsatisfactory. A typical feature of CCA is
the presence of a complex tumor microenvironment (TME) composed of neoplastic cells, a rich inflammatory
infiltrate, and cancer-associated fibroblasts and desmoplastic matrix that makes it extremely chemoresistant to
traditional chemotherapeutic drugs. In this review, we describe the cell populations within the TME, in particular
those involved in the innate and adaptive immune response and how they interact with tumor cells and with matrix
proteins. The TME is crucial for CCA to mount an immune escape response and is the battlefield where molecularly
targeted therapies and immune therapy, particularly in combination, may actually prove their therapeutic value.
Keywords: Tumor reactive stroma, extracellular matrix, immunotherapy, checkpoint inhibitor, immune escape

INTRODUCTION
Cholangiocarcinoma (CCA) is a highly malignant cancer that can develop from different segments of the
biliary tree. The anatomical classification does not include gallbladder and ampullary cancers and
distinguishes among intrahepatic (iCCA) that develops inside the liver up to the secondary bile ducts
(< 10%), perilar (pCCA, also called Klastin’s tumor) that grows between the secondary biliary branches and
the insertion of the cystic duct into the common bile duct (45%), and distal (dCCA) (45%) that is confined

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