PXD031073

PXD031073 is an original dataset announced via ProteomeXchange.

Title	TRX1-enhanced CAR T cells retain their antitumor functions under pro-oxidative conditions
Description	Immunotherapies with CAR-T cells achieve remarkable success, especially against B-cell malignancies. However, their activity against non-hematopoietic solid tumors is very limited. One central cause of this failure may be that a pro-oxidative tumor microenvironment can downmodulate the activation and migration of T-cells. In contrast to tumor cells, primary T cells have very low levels of antioxidants. This makes them prone to pro-oxidative effects. Oxidation-induced dysregulation of actin cytoskeletal dynamics hinders T-cell migration which allows only low tumor infiltration rates. In addition, the proliferation and the effector functions of T-cells (tumor cell killing) are disrupted. In order to strengthen human CAR-T cells against a pro-oxidative tumor microenvironment, we have increased increase their antioxidant capacity, e.g. by expressing antioxidants. We aimed to characterize the importance of antioxidant empowerment at functional level and at the molecular level. Among the antioxidant systems, thioredoxin1 (TRX1)-empowerment, allowed CAR T cells to retain their capacities for cytolytic immune synapse formation, cytokine release, proliferation, and cytotoxicity under pro-oxidative conditions. At the molecular level, gene expression analysis revealed that a pro-oxidative micromilieu caused a downmodulation of costimulatory and cytokine signals of T cells. One unique focus of this study was also to investigate global influence of reactive oxygen species on protein oxidation in T cells. Therefore, using TRX1 kinetic trapping and consequently mass spectrometry was employed to get insight into global oxidation levels in T cells. This analysis, namely redoxosome analysis, unveiled 196 oxidized proteins which were annotated to regulate several antitumor T cell functions. Taken together, our results provide evidence that TRX1 empowerment can increase CAR T cell efficacy against solid tumors.
HostingRepository	PRIDE
AnnounceDate	2022-11-23
AnnouncementXML	Submission_2022-11-23_03:40:24.334.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	ThomasRuppert
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	N-ethylmaleimide derivatized cysteine; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-19 03:01:31	ID requested
⏵ 1	2022-11-23 03:40:24	announced

Dataset with its publication pending

submitter keyword: CAR T cells, ROS, immunosuppression, Thioredoxin 1,Cancer immunotherapy, redox regulation

ThomasRuppert
contact affiliation	Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) 69120 Heidelberg IM Neuenheimer Feld 282 69120 Heidelberg
contact email	t.ruppert@zmbh.uni-heidelberg.de
lab head
ThomasRuppert
contact affiliation	ZMBH, Im Neuenheimer Feld 282, 69122 Heidelberg
contact email	t.ruppert@zmbh.uni-heidelberg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031073
     1. Label: PRIDE project
     2. Name: TRX1-enhanced CAR T cells retain their antitumor functions under pro-oxidative conditions