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

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.

CIMT 2024: Report on the 21st Annual Meeting of the Association for Cancer Immunotherapy

“…By employing a murine HCC model that faithfully replicates distinct human HCC subclasses, she found that aggressively growing subtypes exhibited more myeloid-dominant and less T-cell infiltrated phenotypes as compared to less aggressively growing subtypes. 14 This was driven by Granulocyte-macrophage colony-stimulating factor (GM-CSF) expression induced downstream of the Nras G12D oncogene and neutralizing GM-CSF in combination with HCC standard of care VEGF blockade synergistically improved survival in mice. In the second part of her talk, Akkari discussed the dynamic co-evolution of cancer and myeloid cells in the mouse RCAS glioma model.…”

Ultra-resolution Deconvolution of Spatial Transcriptomics Unveils Spatiotemporal Cellular Dynamics in Complex Microenvironments

“…Tumor-intrinsic genomic alterations have collateral effects that modify the spatial organization of the immune microenvironment [53][54][55] . To achieve the spatial linking of tumor genomics with diverse immune microenvironments at a detailed clonal resolution, we generated an integrated immunogenomics platform termed 'UCASpatial-clonalTIME'.…”

Cancer cell plasticity defines response to immunotherapy in cutaneous squamous cell carcinoma

“…Several studies have indicated that cancer cell features also influence the tumor immune landscape 13 , 17 – 19 and that, in turn, these immune cells play an important role in tumor progression, invasion, and metastasis 20 – 22 . Indeed, tumors enriched in the EMT, focal adhesion, extracellular matrix remodeling, angiogenesis, inflammation, and hypoxia signatures are associated with increased infiltration of immunosuppressive cell populations (such as myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells, and M2-like macrophages) 23 , 24 and expression of multiple inhibitory molecules such as immune checkpoint (IC) ligands 25 , 26 .…”