Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy.

Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings.

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© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.

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Competing interests: JBA is a member of the scientific advisory board at SEALD, Norway and reports scientific consultancies for QED Therapeutics and Flagship Pioneering. JBA has received research funding from Incyte. CB received honoraria as speaker (Astrazeneca, Incyte) and consultant (Incyte, Servier, Boehringer Ingelheim, Astrazeneca), received research funds (Avacta, Medannex, Servier) and her spouse is an employee of Astrazeneca. JML is receiving research support from Eisai, Bayer HealthCare Pharmaceuticals, Ipsen, and consulting fees from Eisai, Merck, Bristol-Myers Squibb, Eli Lilly, Roche, Genentech, Ipsen, Glycotest, AstraZeneca, Bayer HealthCare Pharmaceuticals, Omega Therapeutics, Mina Alpha, Boston Scientific, Exelixis, Bluejay and Captor Therapeutics. RM has received consulting and lecture fees from Servier and Roche and travel and education funding from MSD, Eli Lilly, Bayer, Roche, Astrazeneca. AL reports receiving consulting fees from Intercept Pharma, Alfa Sigma, Takeda, and Albireo Pharma, and speakers’ fees from Gilead, Abbvie, MSD, Intercept Pharma, AlfaSigma, GSK and Incyte.