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Myeloid-specific SHP-2 ablation alters the fate commitment of myeloid cells and induces anti-tumor immunity

ABSTRACT: We generated mice with conditional targeting of the Ptpn11 gene (encoding for Shp-2) in T cells (Shp-2fl/flLckCre) or myeloid cells (Shp-2fl/flLysMCre). Although no difference in tumor growth was observed between Shp-2fl/flLckCre and control mice and both groups were similarly benefitted by PD-1 blockade, Shp-2fl/flLysMCre mice had significantly diminished tumor growth that was not further decreased by anti-PD-1 treatment. As revealed by RNA-seq, myeloid-specific Shp-2 ablation was paralleled by expansion of activated myeloid cells and macrophages with molecular signatures of enhanced neutrophil and macrophage differentiation, phagocytosis, antigen-presenting function, TLR and type I IFN signaling, chemokine production, and expression of immunostimulatory molecules, which promoted T cell recruitment and activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE187394 | GEO | 2022/10/26

REPOSITORIES: GEO

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Myeloid-specific ablation of Pdcd1 alters fate comittment of tumor-associated macrophages and induces anti-tumor immunity

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Concomitant deletion of Shp-1 and Shp-2 in T cells fails to improve anticancer responses

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2022-09-29 | PXD034897 | Pride

Targeting PDGFRa-activated Glioblastoma through Specific Inhibition of SHP-2-mediated Signaling

Project description:SHP-2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is critical for PDGFR-driven gliomagenesis. SHP099, a novel and potent SHP-2 inhibitor, preferentially attenuated the tumorigenicity of GBM and glioma stem-like cells (GSCs) compared to normal brain cells or neural progenitor cells in vitro. Delivered orally, SHP099 crosses the blood-brain barrier (BBB) and accumulates at efficacious concentrations in the brains, as determined using two different orthotopic xenograft models. SHP099 inhibited tumor growth and extended survival in activated PDGFR-signaling xenografts alone and in combination with first-line chemotherapeutic agent, temozolomide (TMZ). This study highlights SHP-2 inhibitor SHP099 potential for treatment of clinical GBM in combination with TMZ.

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Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.

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Project description:Checkpoint immunotherapy unleashes T cell effector functions that control tumor growth, but can be undermined by myeloid cells that induce immunosuppression. TREM2 is a myeloid surface receptor that binds lipids and transmits intracellular signals through protein-tyrosine phosphorylation known to sustain microglial responses during Alzheimer’s disease. Intriguingly, TREM2 expression has recently been noted in tumor-infiltrating macrophages. We found that Trem2–/– mice are more resistant to growth of sarcoma, colorectal and mammary cancer cells than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and led to complete tumor regression when combined with anti-PD-1. scRNA-seq revealed that both constitutive TREM2 deficiency and anti-TREM2 are associated with relatively scant representation of MRC1+ and CX3CR1+ subsets in the macrophage tumor infiltrate, paralleled by expansion of subsets expressing immunostimulatory molecules. These changes were associated with improved T cell responses. TREM2 expression was evident in tumor macrophages in over 200 human cancer cases examined and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 is a promising target to modify tumor-infiltrating myeloid cells and effectively augment checkpoint immunotherapy.

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Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

2010-12-10 | GSE20599 | GEO

RNA sequencing of SHP -/- knockout mouse transcriptome

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2013-10-22 | E-GEOD-43893 | biostudies-arrayexpress

Microarray analysis of genes regulated by SHP in wild-type and ob/ob mice.

Project description:Liver gene expression was compared in wild type, SHP knockout, ob/ob, and ob/ob SHP double mutant mice.

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Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2

Project description:Background: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, Small Heterodimer Partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19. Genome-wide SHP binding profiles in hepatic chromatin in mice under treatment of FGF19 or vehicle were generated using high throughput sequencing followed by chromatin immunoprecipitation.

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Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut

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2022-04-22 | GSE197549 | GEO

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