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Ptpn2 regulates the generation of cytotoxic Tim-3+ CD8+ T cells and restrains anti-tumor immunity

ABSTRACT: Ptpn2 regulates the generation of cytotoxic Tim-3+ CD8+ T cells and restrains anti-tumor immunity

PROVIDER: PRJNA488638 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7770672_1.fastq.gz	Fastqsanger.gz
	SRR7770672_2.fastq.gz	Fastqsanger.gz
	SRR7770673_1.fastq.gz	Fastqsanger.gz
	SRR7770673_2.fastq.gz	Fastqsanger.gz
	SRR7770674_1.fastq.gz	Fastqsanger.gz

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Ptpn2 regulates the generation of cytotoxic Tim-3+ CD8+ T cells and restrains anti-tumor immunity

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Expression analysis of Tim-3 knockdown RAW264.7 cell

Project description:Investigation of whole genome gene expression level changes in a Tim-3 knockdown RAW264.7 cell, compared to control siRNA transfected RAW264.7 cell. The Tim-3 knockdown of this cell render it hyper-reactive to TLR stimulation. Tim-3 knockdown analyzed in this study are further described in Li Y, Feng J, Geng S, Geng S, Wei H, Chen G, Li X, Wang L, Wang R, Peng H, Han G, Shen B, Li Y. 2011. The N- and C-terminal carbohydrate recognition domains of galectin-9 contribute differently to its multiple functions in innate immunity and adaptive immunity. Mol Immunol. 48(4):670-7. (PID 21146220) A six chip study using total RNA recovered from Tim-3 knockdown and control RAW264.7 cells. There are 135,000 probes in a chip,each chip measures the expression level of 27526 genes of mouse from Nimblegen. Fold-change screening between the two groups obtained from the experiment. The threshold used to screen up or down regulated genes is Fold changeM-oM-<M-^-oM-<M-^]2.0

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The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_ATACseq]

Project description:Immune checkpoint blockade is effective for some cancer patients, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets and in particular, the active site has been considered undruggable. Here, we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In murine cancer models resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes NK and CD8+ T cell function by enhancing JAK-STAT signaling and reducing T cell dysfunction. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (NCT04777994). More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes.

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The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_RNAseq]

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The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [SK_RNAseq]

Project description:AC484 is a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. In order to investigate the response of AC484 and IFNg treatment on wild type and PTPN2/N1 dual deletion B16F10 cells, these tumours were transcriptionally profiled.

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