Chimeric Antigen Receptor T Cell Therapy Targeting Epithelial Cell Adhesion Molecule in Gastric Cancer: Mechanisms of Tumor Resistance.
CAR T cell imaging
CAR T cell therapy
EpCAM
single-cell multiomics
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
23 Nov 2023
23 Nov 2023
Historique:
received:
07
10
2023
revised:
12
11
2023
accepted:
14
11
2023
medline:
9
12
2023
pubmed:
9
12
2023
entrez:
9
12
2023
Statut:
epublish
Résumé
Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-
Identifiants
pubmed: 38067255
pii: cancers15235552
doi: 10.3390/cancers15235552
pmc: PMC10705754
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NIH HHS
ID : R01-CA217059
Pays : United States
Organisme : NIH HHS
ID : R01-CA254035
Pays : United States
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