Reduction of fibrosis and immune suppressive cells in ErbB2-dependent tumorigenesis by an LXR agonist

Abstract

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent immune surveillance. One such element associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix that elicit an immune tolerant microenvironment. To address the role of fibrosis in tumorigenesis, we developed NeuT/ATTAC transgenic mice expressing a constitutively active NeuT/erbB2 transgene, and an inducible, fat-directed caspase-8 fusion protein, which upon activation results in selective and partial ablation of mammary fat and its replacement with fibrotic tissue. Induction of fibrosis in NeuT/ATTAC mice led to more rapid tumor development and an inflammatory and fibrotic stromal environment. In an effort to explore therapeutic options that could reduce fibrosis and immune tolerance, mice were treated with the oxysterol liver X receptor (LXR) pan agonist, N,N-dimethyl-3-β-hydroxy-cholenamide (DMHCA), an agent known to reduce fibrosis in non-malignant diseases. DMHCA reduced tumor progression, tumor multiplicity and fibrosis, and improved immune surveillance by reducing infiltrating myeloid-derived suppressor cells and increasing CD4 and CD8 effector T cells. These effects were associated with downregulation of an LXR-dependent gene network related to reduced breast cancer survival that included Spp1, S100a9, Anxa1, Mfge8 and Cd14. These findings suggest that the use of DMHCA may be a potentially effective approach to reduce desmoplasia and immune tolerance and increase the efficacy of cancer therapy.

Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression

“…RNA was extracted, its quality assessed and RNAseq performed by Novagene as previously described [ 21 , 42 ]. Raw data quality was checked using FastQC (v0.11.9), and adapter trimming of raw data was performed using Cutadapt (v3.5).…”

Breaking Barriers: The Promise and Challenges of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

“…Fibrosis, the excessive deposition of extracellular matrix components, is commonly associated with chronic inflammation and tissue remodeling [40]. In the context of TNBC, fibrosis contributes to the formation of a dense and fibrotic TME, creating a barrier that can impede effective drug delivery and immune cell infiltration [41]. Paradoxically, this fibrotic response also plays a crucial role in the establishment of immunosuppressive mechanisms within the TME.…”

Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy

“…Transgenic mice [25] with constitutive active NeuT/ErbB2 and fat-inducible caspase-8 suffer from loss of mammary fat and progressive deposition of the extracellular matrix, resulting in fibrosis and breast cancer. In this inflamed and immunotolerant tumor milieu, pan-LXR agonist DMHCA (N,N-dimethyl-3-β-hydroxy-cholenamide) attenuated tumor growth, desmoplasia, and fibrosis.…”

“…In mouse bone marrow-derived macrophages, LXR represents a downstream target of PI3K-AKT-mTOR signaling [26]. Specifically, the synthesis of natural LXR ligands (e.g., 25-hydroxycholesterol) depended on the lysosomal adaptor protein Lamtor1, which forms an amino acid sensor complex with lysosomal vacuolar-type H+ATPase and mTORC1, promoting M2 polarization of macrophages. Vice versa, Lamtor1 gene depletion, starvation, or ATPase/mTOR inhibition favored M1 polarization.…”