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

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

PROVIDER: PRJNA1125449 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29460821_1.fastq.gz	Fastqsanger.gz
	SRR29460821_2.fastq.gz	Fastqsanger.gz
	SRR29460822_1.fastq.gz	Fastqsanger.gz
	SRR29460822_2.fastq.gz	Fastqsanger.gz
	SRR29460823_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

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

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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

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

2024-06-18 | PXD053192 |

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

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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Oncolytic virus M1 functions as a bi-functional checkpoint inhibitor to enhance the antitumor activity of DC vaccine

Project description:Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic viruses are considered to be an ideal strategy to overcome immunosuppression and expose TAAs, therefore they may work synergistically with DC vaccines. In this study, we demonstrated that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccine in a variety of syngeneic tumor mouse models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we identified that tumor cells offset the function of DC vaccines through the myeloid immune checkpoint SIRPα-CD47, while OVM can downregulate the expression of SIRPα and CD47 in DCs and tumor cells, respectively. Based on the fact that OVM upregulates the expression of PD-L1 in DCs, PD-L1 blockade was introduced with the combination of DC vaccines and OVM, resulting in a further potentiation of antitumor activity. Overall, we revealed that OVM can strengthen the antitumor efficacy of DC vaccines by targeting the immune checkpoint SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.

2023-09-01 | GSE222080 | GEO

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