PXD037546

PXD037546 is an original dataset announced via ProteomeXchange.

Title	Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance
Description	Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:41:06.393.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD037546
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-19 02:38:50	ID requested
1	2023-03-11 02:54:19	announced
⏵ 2	2023-11-14 08:41:08	announced	2023-11-14: Updated project metadata.

Sridaran D, Chouhan S, Mahajan K, Renganathan A, Weimholt C, Bhagwat S, Reimers M, Kim EH, Thakur MK, Saeed MA, Pachynski RK, Seeliger MA, Miller WT, Feng FY, Mahajan NP, Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nat Commun, 13(1):6929(2022) [pubmed]

10.6019/PXD037546;

submitter keyword: Phosphotyrosine, Immune Checkpoint Blockade, ACK1,Prostate Cancer, SRC

Nupam Mahajan, PhD
contact affiliation	Siteman Cancer Center Washington University in St. Louis
contact email	nupam@wustl.edu
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
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/2023/03/PXD037546

PRIDE project URI

• PRIDE
  1. PXD037546
     1. Label: PRIDE project
     2. Name: Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance