Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications.

Autor:	Martin-Serrano MA; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Kepecs B; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Torres-Martin M; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Catalunya, Spain., Bramel ER; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Haber PK; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Merritt E; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; The Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, New York, USA., Rialdi A; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Param NJ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Maeda M; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Lindblad KE; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; The Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Carter JK; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Barcena-Varela M; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; The Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Mazzaferro V; General Surgery and Liver Transplantation Unit, Department of Oncology and Hemato-Oncology, University of Milan and Istituto Nazionale Tumori, IRCCS Foundation, Milano, Lombardia, Italy., Schwartz M; Department of Surgery, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Affo S; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain., Schwabe RF; Department of Medicine, Columbia University, New York, New York, USA., Villanueva A; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Guccione E; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Friedman SL; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Lujambio A; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; The Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Tocheva A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; The Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, New York, USA., Llovet JM; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Catalunya, Spain.; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain., Thung SN; Department of Pathology, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Tsankov AM; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Sia D; Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA daniela.sia@mssm.edu.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2023 Apr; Vol. 72 (4), pp. 736-748. Date of Electronic Publication: 2022 May 18.
DOI:	10.1136/gutjnl-2021-326514
Abstrakt:	Objective: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment ('STIM' classification). Design: We applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease. Results: iCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p<0.001). Analysis of cell-cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-like class (~35%) is enriched in 'M2-like' macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class ( tumour classical : ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS -mutant iCCA murine model to anti-PD1 therapy. Conclusions: We describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies. Competing Interests: Competing interests: JML is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca. AV has received consulting fees from Genentech, Guidepoint, Fujifilm, Boehringer Ingelheim, FirstWord, and MHLife Sciences; advisory board fees from Exact Sciences, Nucleix, Gilead and NGM Pharmaceuticals; and research support from Eisai. (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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