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

Christel F. A. Ramirez, Daniel Taranto, Masami Ando-Kuri, Marnix H. P. Groot, Efi Tsouri, Zhijie Huang, Daniel Groot, Roelof J. C. Kluin, Daan J. Kloosterman, Joanne Verheij, Jing Xu, Serena Vegna () and Leila Akkari ()
Additional contact information
Christel F. A. Ramirez: The Netherlands Cancer Institute
Daniel Taranto: The Netherlands Cancer Institute
Masami Ando-Kuri: The Netherlands Cancer Institute
Marnix H. P. Groot: The Netherlands Cancer Institute
Efi Tsouri: The Netherlands Cancer Institute
Zhijie Huang: Sun Yat-sen University Cancer Center
Daniel Groot: The Netherlands Cancer Institute
Roelof J. C. Kluin: The Netherlands Cancer Institute
Daan J. Kloosterman: The Netherlands Cancer Institute
Joanne Verheij: University of Amsterdam
Jing Xu: The Netherlands Cancer Institute
Serena Vegna: The Netherlands Cancer Institute
Leila Akkari: The Netherlands Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract 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, NrasG12D-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow 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.

Date: 2024
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DOI: 10.1038/s41467-024-46835-2

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