PXD053192
PXD053192 is an original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2024-06-18 01:23:19 | ID requested | |
⏵ 1 | 2024-06-18 01:24:32 | announced |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Proteome, Ubiquitin-Modified Proteome, KPC-sgCtrl cells, KPC-sgUbe2d3-1 cells |
Contact List
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 |
Full Dataset Link List
iProX dataset URI |