Dataset Information

Cholangiocarcinoma: what are the most valuable therapeutic targets - cancer-associated fibroblasts, immune cells, or beyond T cells?

ABSTRACT:

Introduction

CCAs are dense and desmoplastic tumors with an abundant tumor microenviroment (TME). The evolving TME is characterized by reciprocal interactions between cancer cells and their environment and is essential in facilitating tumor progression. The TME has nonimmune and immune components. Nonimmune cell types include cancer-associated fibroblasts (CAFs) and endothelial cells accompanying tumor angiogenesis. Immune cell types include elements of the innate and adaptive immune response, and can have pro-tumor or antitumor roles. The TME can shape treatment response and resistance. Therefore, elements of the TME are attractive therapeutic targets. TME targeting therapies have been evaluated in preclinical and clinical studies but only a small subset of patients has a meaningful response.

Areas covered

We discuss the TME components and potential TME targeting strategies. Literature search was performed on PubMed and ClinicalTrials.gov until October 2021.

Expert opinion

Elucidating the CCA TME is essential for developing effective treatment strategies. Preclinical models that recapitulate the disease (such as organoids) are important tools in uncovering the intricate cross talk in the CCA TME. Characterization of patient-derived specimens using multi-omic and single-omic technologies can dissect the cellular interplay in the CCA TME, which can guide development of effective treatment strategies and identify biomarkers for patient stratification.

SUBMITTER: Wang J

PROVIDER: S-EPMC9239407 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsCholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies.MethodsAn integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC.ResultsKRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFβ signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors.ConclusionAn integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches.Lay summaryTargeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.