Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy

ABSTRACT

Introduction: Cholangiocarcinomas (CCAs) are biliary epithelial tumors with rising incidence over the past 3 decades. Early diagnosis of CCAs remains a significant challenge and the majority of patients present at an advanced stage. CCAs are heterogeneous tumors and currently available standard systemic therapy options are of limited effectiveness. Immune checkpoint inhibition (ICI) has transformed cancer therapy across a spectrum of malignancies. However, the response rate to ICI has been relatively disappointing in CCAs owing to its desmoplastic tumor microenvironment (TME).

Areas covered: Tumor microenvironment of CCAs consists of innate and adaptive cells, stromal cells, and extracellular components (cytokines, chemokines, exosomes, etc.). This intricate microenvironment has multiple immunosuppressive elements that promote tumor cell survival and therapeutic resistance. Accordingly, there is a need for the development of effective therapeutic strategies that target the TME. Herein, we review the components of the CCA TME, and potential therapies targeting the CCA TME.

Expert opinion: CCAs are desmoplastic tumors with a dense tumor microenvironment. An enhanced understanding of the various components of the CCA TME is essential in the effort to develop novel biomarkers for patient stratification as well as combination therapeutic strategies that target the tumor plus the TME.

KEYWORDS:

• Cancer-associated fibroblasts
• myeloid-derived suppressor cells
• tumor-associated macrophages
• immune checkpoint inhibition

Article highlights

• CCA is a highly lethal, difficult-to-diagnose malignancy with limited treatment options.

• Tumor-associated macrophages (TAMs) are an integral component of the CCA tumor immune contexture, and play an essential role in cancer progression and remodeling of the microenvironment.

• Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with potent immunosuppressive properties, and MDSC populations expand in a variety of malignancies including CCA.

• The early results of immune checkpoint inhibition (ICI) monotherapy in CCA have been disappointing, likely owing to its dense, desmoplastic microenvironment that contains an abundance of immunosuppressive elements such as TAMs and MDSCs.

• Cancer-associated fibroblasts (CAFs) play a crucial role in mediating CCA growth and progression, and therapeutic targeting of CAFs is a promising approach for the treatment of CCA.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This manuscript was funded by the National Institutes of Health (NIH) (K08CA236874-01), American Gastroenterology Association Research Scholar Award, Center for Biomedical Discovery Team Science Award, Hepatobiliary Cancer SPORE (P50 CA210964) Career Enhancement Program, Mayo Center for Cell Signaling in Gastroenterology (P30DK084567), and the Mayo Foundation.