Targeting tumor microenvironment for cholangiocarcinoma: Opportunities for precision medicine

Abstract

Systemic treatments (e.g., chemotherapy and targeted therapies) have limited efficacy for patients with locally advanced - unresectable - and metastatic cholangiocarcinoma (CCA), with an overall survival of less than a year. Tumor microenvironment (TME) represents the ecosystem surrounding the tumor which comprises immune cells, fibroblasts, endothelial cells, and a wide range of soluble factors. CCA TME is characterized by an abundant desmoplastic stroma, exhibits a high heterogeneity and it plays a central role in cancer onset and progression. There is growing evidence suggesting that it is possible to target TME in association with other treatment modalities, such as cytotoxic chemotherapy or targeted therapies, paving the way to possible combination strategies with a synergistic effect. Herein, we describe the components of CCA TME - such as cancer-associated fibroblasts and other cells of pivotal importance - with their most relevant interactions, focusing on the preclinical rationale for the development of effective anticancer treatments.

Keywords: Cancer associated fibroblasts; Cholangiocarcinoma; Immunotherapy; Tumor associated macrophages; Tumor infiltrating lymphocytes; Tumor microenvironment.

Graphical abstract

Fig. 1

CCA cells recruit CAFs via the production of several mediators, such as PDGF-D and TGF-β1. In addition, PDGF-D, upon binding its receptor on CAFs, stimulates the release of VEGF-C and VEGF-A resulting in increased angiogenesis and CCA cells intravasation. CAFs promote tumor progression through the release of several mediators, such as HB-EGF and PDGF-B. HB-EGF binds EGFR determining an enhanced invasion of CCA cells and the release of TGF-β1. PDGF-B, upon binding its receptor on CCA cells, protects cancer cells from apoptosis. CAFs recruit MDSCs via the release of CCL2.

Fig. 2

Tregs are induced by MDSCs, TAMs and TANs via the production of IL-10 and CCL2 They determine a polarization of DCs towards an immature immunosuppressive phenotype resulting in an impaired antigen presentation and determining an immune-tolerant microenvironment. In addition, IL-10 induces a polarization of CD4+ T cells towards Th2 response. TGF-β, which is produced by CCA cells and TAMs, play a central role in immunotolerance by enhancing activity of Tregs and via the inhibition of CD8+ T cells. TAMs-derived VEGF reduces CD8+ T cells activity by inducing their FasL-mediated killing. CCA cancer stem cells are able to induce TAMs polarization towards a tumor-promoting phenotype, on the other hand activated TAMs could stimulate CCA cells proliferation via the Wnt/β-catenin pathway. CCA-derived CXCL9 enhance NK cells recruitment, thus resulting in an improved immune response.