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

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

PROVIDER: PRJNA777536 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16761284_1.fastq.gz	Fastqsanger.gz
	SRR16761284_2.fastq.gz	Fastqsanger.gz
	SRR16761285_1.fastq.gz	Fastqsanger.gz
	SRR16761285_2.fastq.gz	Fastqsanger.gz
	SRR16761286_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

Project description:Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1). Blockade of PD-1 signalling leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase Src homology 2 (SH2) domain–containing phosphatase (SHP)-2 is essential for the molecular cascade downstream PD-1, suggesting functional redundancy with the homologous phosphatase SHP-1. Therefore, we investigated the effect of concomitant SHP-1 and 2 deletion in T cells by knocking out these phosphatases under the CD4cre promoter. In vivo results not only indicate that Shp-1/2 deletion is insufficient to ameliorate tumour control, but also that it impairs the therapeutic effects of anti-PD1 treatment, affecting tumour-infiltrating CD8+ T cells. Notably, acute deletion of Shp-1/2 in effector T cells also fails to improve tumour control. In vitro results show that Shp-1/2-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analysis reveals substantial alterations in their proteome, including in apoptosis-related pathways. This data indicates that concomitant ablation of SHP-1/2 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.

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

Project description:We generated mice with conditional targeting of the Pdcd1 gene (encoding for PD-1) in myeloid cells (Pdcd1-2fl/flLysMCre). Pdcd1-2fl/flLysMCre mice had significantly diminished tumor growth. As revealed by RNA-seq, myeloid-specific Pdcd1 ablation was paralleled by generation of myeloid cells with monocytic dominance, and activated macrophages with molecular signatures of enhanced myeloid cell differentiation, macrophage activation, phagocytosis, TLR and NF-kB signaling, chemokine and cytokine production, and expression of immunostimulatory molecules.

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

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

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

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Project description:The protein-tyrosine phosphatase SHP-1 (PTPN6) is an important glucose homeostasis modulator. Besides negatively regulating insulin signaling, the specific role of SHP-1 in metabolic control remains poorly understood. We show that SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene, thereby modulating basal gluconeogenesis in hepatocytes. SHP-1 interacts with RNA polymerase II-subunits and signal transducer and activator of transcription 5 (STAT5), and localizes to the nucleus, where a sub-fraction of SHP-1 associates with chromatin. While SHP-1 binds to the PCK1-promoter, its loss affects RNA polymerase II-recruitment to this and other promoters of genes enriched for glucose metabolism-related functions. SHP-1-downregulation, and similarly STAT5 pharmacological inhibition reduce PCK1-transcript levels correlating with blunted gluconeogenesis. Overall, we identified a novel molecular SHP-1-function, that of a regulator of PCK1-transcription and subsequently hepatic gluconeogenesis, through physical interaction with the transcription machinery, mediated by an Akt-independent mechanism, but independent of STAT5 tyrosine-phosphorylation status.

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

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TREM1 deficiency alters the tumor myeloid landscape

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