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UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity

ABSTRACT: UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity

PROVIDER: PRJNA1124987 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29445089_1.fastq.gz	Fastqsanger.gz
	SRR29445089_2.fastq.gz	Fastqsanger.gz
	SRR29445090_1.fastq.gz	Fastqsanger.gz
	SRR29445090_2.fastq.gz	Fastqsanger.gz
	SRR29445091_1.fastq.gz	Fastqsanger.gz

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UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity II

Project description:UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity II

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UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity

Project description:Ubiquitylation is pivotal in regulating cellular responses, with its aberration implicated in tumor immune evasion. However, the impact of ubiquitin-conjugating enzymes (E2s) on this evasion remains unclear. Here, we employ a systematic approach to demonstrate that in pancreatic ductal carcinoma (PDAC), the inflammatory microenvironment induces overexpression of the E2 enzyme UBE2D3, contributing to tumor progression through non-oncogene codependent disorders. Through gene expression analyses and functional investigations, we elucidate a mechanism wherein cancer cells evade T cell immune responses by UBE2D3 binding to the ubiquitin ligase KLHL13 to co-ubiquitinate TAP2. This K63-linkage ubiquitination at the lysine 245 site of TAP2 impedes antigenic peptide transport by the TAP1/TAP2 complex, hindering p-MHC assembly and presentation in cancer cells. We demonstrate that genetic inhibition of UBE2D3 enhances tumor-specific CD8+ T cell proliferation and extends effector-memory-like phenotypes. Building on this, we develop a small-molecule inhibitor, QX-6, targeting the active site of UBE2D3 to disrupt its function. Pharmacologic inhibition of UBE2D3 blocks the ubiquitylation of antigen presentation-related substrates, leading to increased p-MHC presentation by cancer cells and reduced T cell exhaustion. Using immunocompetent and humanized models, we elucidate the therapeutic efficacy of targeting UBE2D3. Furthermore, we evaluate the synergistic anti-tumor effects of QX-6 in combination with KRAS-targeted TCR-T cell immunotherapy. In summary, our study reveals a post-translational modification mechanism wherein the intracellular checkpoint UBE2D3 regulates the TAP2 switch to control cancer cell evasion of CTLs, presenting a potential immunotherapeutic strategy to improve PDAC treatment outcomes.

2024-06-21 | GSE270097 | GEO

UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity II

2024-06-23 | GSE270228 | GEO

RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumor immunity

Project description:RIG-I is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity remains unclear. Here, we demonstrate that RIG-I is upregulated in tumor infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T cell function and limit antitumor immunity. Mechanically, up-regulation of RIG-I in CD8+ T cells is induced by retinoic acid (RA), a metabolite of vitamin A in TME, and direct inhibits the AKT/glycolysis signaling pathway. In addition, deletion of RIG-I enhances the efficacy of adoptively transferred T cells against solid tumors and inhibition of RIG-I enhances the response to PD-1 blockade. Our findings identify RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with immune checkpoint blockade.

2023-04-25 | GSE230045 | GEO

UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity

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RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumor immunity

Project description:RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumor immunity

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IFN gamma signaling in cytotoxic T cells restricts antitumor responses by inhibiting the maintenance and clonality of intra-tumoral stem-like T cells

Project description:IFN gamma signaling in cytotoxic T cells restricts antitumor responses by inhibiting the maintenance and clonality of intra-tumoral stem-like T cells

2022-12-16 | GSE221118 | GEO

STUB1 is an intracellular checkpoint for interferon gamma sensing

Project description:STUB1 is an intracellular checkpoint for interferon gamma sensing

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A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

Project description:A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

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