PXD053192-1

PXD053192 is an original dataset announced via ProteomeXchange.

Title	UBE2D3 is an Intracellular Checkpoint in Pancreatic Ductal Carcinoma that Restricts CD8+ T-Cell Antitumor Immunity
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.
HostingRepository	iProX
AnnounceDate	2024-06-18
AnnouncementXML	Submission_2024-06-18_01:24:32.444.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shiqun Wang
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	ubiquitination signature dipeptidyl lysine
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-18 01:23:19	ID requested
⏵ 1	2024-06-18 01:24:32	announced

Dataset with its publication pending

submitter keyword: Proteome, Ubiquitin-Modified Proteome, KPC-sgCtrl cells, KPC-sgUbe2d3-1 cells

Jiangjiang Qin
contact affiliation	Hangzhou Institute of Medicine, Chinese Academy of Sciences
contact email	jqin@ucas.ac.cn
lab head
Shiqun Wang
contact affiliation	Hangzhou Institute of Medicine, Chinese Academy of Sciences
contact email	shiqun_wang@outlook.com
dataset submitter

iProX dataset URI