PXD079073

PXD079073 is an original dataset announced via ProteomeXchange.

Title	IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma
Description	Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
HostingRepository	PRIDE
AnnounceDate	2026-05-30
AnnouncementXML	Submission_2026-05-30_12:11:02.726.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD079073
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-29 17:33:03	ID requested
⏵ 1	2026-05-30 12:11:03	announced

10.6019/PXD079073;

submitter keyword: Macrophages, B Cell Lymphoma,Interferon, iNOS, Chimeric Antigen Receptor T Cell

Marco Davila
contact affiliation	Roswell Park Cancer Center Buffalo, NY, USA
contact email	Marco.Davila@RoswellPark.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD079073
     1. Label: PRIDE project
     2. Name: IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma