PXD057519

PXD057519 is an original dataset announced via ProteomeXchange.

Title	p-FADD-CD8+T cell axis determines hepatocellular carcinoma response to immune checkpoint inhibitors
Description	The heterogenicity of hepatocellular carcinoma (HCC) remains a key obstacle in turning the majority of ‘immune-cold’ tumors ‘hot’ for effective immune checkpoint inhibitors (ICIs). Through analyzing the naturally-existed ‘hot’ HCC variants, we identified fas-associated death domain (FADD) as a key molecule upregulated in patients with dense tumor-filtrating CD8+T cells and better response to ICIs. Apart from the canonical role in apoptosis pathway, our data showed that CRISPR knockout of hepatoma-intrinsic Fadd led to increased tumor weights in immunocompetent but not immunodeficient mice, accompanied with decreased numbers and IFN-γ/TNF-ɑ production of tumor-filtrating CD8+T cells. Mechanistically, phosphorylated FADD translocated into cell nucleus, where it interacted with Sam68 to upregulate NF-κB transcription of CCL5, thereby promoted CD8+T cell tumor infiltration. Interestingly, anti-PD1 triggered FADD phosphorylation by CD8+T cell-derived IFN-γ/TNF-ɑ in ICI-sensitive, but not resistant tumors. Sequential FADD activation through genetic or pharmacologic approaches to orchestrate p-FADD-CD8+T cell axis therefore overcame ICI resistance in ICI-resistant orthotopic and spontaneous HCC mouse models in vivo. Taken together, our findings may provide insights into the combinatory immunotherapy approaches for the majority of HCC patients in the future.
HostingRepository	PRIDE
AnnounceDate	2025-07-07
AnnouncementXML	Submission_2025-07-06_23:14:01.645.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Ting Hei Chan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-05 00:21:22	ID requested
⏵ 1	2025-07-06 23:14:02	announced

Dataset with its publication pending

ProteomeXchange project tag: Human Proteome Project

submitter keyword: HCC,FADD, Hepg2

Jingying Zhou
contact affiliation	School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
contact email	zhoujy@cuhk.edu.hk
lab head
Thomas Ting Hei Chan
contact affiliation	School of Biomedical Sciences, The Chinese University of Hong Kong
contact email	tingheithomas@link.cuhk.edu.hk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/07/PXD057519

PRIDE project URI

• PRIDE
  1. PXD057519
     1. Label: PRIDE project
     2. Name: p-FADD-CD8+T cell axis determines hepatocellular carcinoma response to immune checkpoint inhibitors