Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma.

Autor: Ramirez CFA; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Taranto D; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Ando-Kuri M; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., de Groot MHP; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Tsouri E; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Huang Z; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China., de Groot D; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Kluin RJC; Genomics Core facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Kloosterman DJ; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Verheij J; Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands., Xu J; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China., Vegna S; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. s.vegna@nki.nl.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. s.vegna@nki.nl., Akkari L; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. l.akkari@nki.nl.; Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. l.akkari@nki.nl.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 22; Vol. 15 (1), pp. 2581. Date of Electronic Publication: 2024 Mar 22.
DOI: 10.1038/s41467-024-46835-2
Abstrakt: Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics' specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, Nras G12D -driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a Nras G12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6C low cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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