PXD058491-1

PXD058491 is an original dataset announced via ProteomeXchange.

Title	Inhibition of Furin in CAR macrophages directs them towards a pro-inflammatory phenotype and enhances their anti-tumor activities.
Description	Anti-cancer immunotherapy approaches are increasingly coveted. Chimeric antigen receptor (CAR)-T cell therapy has been shown to be an effective treatment for hematological tumors, but the treatment of solid tumors still lacks effectiveness, due to lower intra-tumor infiltration of CAR-T cells and tumor-induced immunosuppression. Macrophages represent a very large proportion of the tumor environment, participate in many aspects to tumor development and therefore represent interesting therapeutic targets. Macrophages can infiltrate solid tumor tissue and interact with almost all cellular components in the tumor microenvironment. In addition, macrophages can also promote a direct anti-tumor response by phagocyting tumor cells. We have developed macrophages expressing a CAR receptor against the HER2 antigen. The CAR receptor possesses an intracellular domain CD3ζ having homology with the protein FcεRI-γ, which once activated by the recognition antibody-antigen, induces the phagocytic activity of macrophages. 72% of macrophages express the CAR after transduction. CAR-M can specifically phagocyte HER2 coated-beads in a much more effective way than WT macrophages. We have then confirmed the capacity of CAR-M to phagocyte HER2+ cancer cell lines. Co-culture of CAR-M with breast cancer tumoroids (HER2+ or HER2-) has also been performed demonstrating their efficacy in a more complex environment. However, in the tumor microenvironment, due to their plasticity, macrophages tend to adopt an anti-inflammatory phenotype losing their anti-tumor activities. We have therefore developed a combined strategy by inhibiting two proprotein convertases, Furin and PC1/3 in CAR-M. The inhibition of furin or PC1/3 induces an increase in pro-inflammatory markers and maintains macrophage activation in the presence of cancer cells. In addition, HER2+ CAR-M with shFurin or shPC1/3 greatly increases the phagocytic activity on Her2+ beads or Her2+ tumors. These enzymes are therefore phenotypic regulators of macrophages. Our strategy is therefore based on a double activation of tumor-infiltrating macrophages. The first one consists in boosting the phagocytic activity of macrophages by having them express a CAR receptor targeting a tumor antigen. The second allows their reprogramming towards a pro- inflammatory phenotype by the inhibition of Furin and/or PC1/3 proprotein convertases
HostingRepository	PRIDE
AnnounceDate	2024-12-12
AnnouncementXML	Submission_2024-12-12_09:00:03.394.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lydia Ziane chaouche
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF fleX; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-02 14:36:27	ID requested
⏵ 1	2024-12-12 09:00:03	announced

10.1038/S41419-024-07267-4;

ProteomeXchange project tag: Human Proteome Project

submitter keyword: Proprotein convertases, Furin,Breast cancer, CAR macrophage, tumoroids

Michel Salzet
contact affiliation	PRISM U1192, Universite de Lille France (Lab head)
contact email	michel.salzet@univ-lille.fr
lab head
Lydia Ziane chaouche
contact affiliation	PRISM Laboratory Univ lille
contact email	lydia.zianechaouche@univ-lille.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058491
     1. Label: PRIDE project
     2. Name: Inhibition of Furin in CAR macrophages directs them towards a pro-inflammatory phenotype and enhances their anti-tumor activities.