PXD058699

PXD058699 is an original dataset announced via ProteomeXchange.

Title	Restoration of LAT activity improves CAR T-cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia
Description	Chimeric antigen receptor (CAR) T-cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by post-CAR relapses. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T-cells and underlies the majority of relapses following CD22BBz CAR T-cell therapy. We interrogated CD22BBz CAR signaling in response to low antigen and found inefficient phosphorylation of LAT, limiting downstream signaling. To overcome this, we designed the Adjunctive LAT-Activating CAR T-cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrated reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling and AP-1 activity. Consequently, ALA-CART cells showed improved cytotoxicity, proliferation, persistence and efficacy against antigen-low leukemias that were refractory to clinically-active CD22BBz CAR T-cells. These data suggest restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T-cell failure.
HostingRepository	PRIDE
AnnounceDate	2025-05-03
AnnouncementXML	Submission_2025-05-02_18:26:42.581.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD058699
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Christopher Ebmeier
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-09 10:05:47	ID requested
⏵ 1	2025-05-02 18:26:43	announced

10.1016/J.CCELL.2025.02.008;

10.6019/PXD058699;

submitter keyword: leukemia,CAR T-cell, phosphoproteomics

Mark Eric Kohler MD PhD
contact affiliation	Assistant Professor, Pediatrics-Heme/Onc and Bone Marrow Transplantation
contact email	mark.kohler@cuanschutz.edu
lab head
Christopher Ebmeier
contact affiliation	University of Colorado Boulder
contact email	christopher.ebmeier@colorado.edu
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/2025/05/PXD058699

PRIDE project URI

• PRIDE
  1. PXD058699
     1. Label: PRIDE project
     2. Name: Restoration of LAT activity improves CAR T-cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia