Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer.
CAR
CAR-NK
CD44v6
TNBC
cancer
immunotherapy
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
20 May 2023
20 May 2023
Historique:
received:
28
03
2023
revised:
12
05
2023
accepted:
16
05
2023
medline:
29
5
2023
pubmed:
27
5
2023
entrez:
27
5
2023
Statut:
epublish
Résumé
There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.
Identifiants
pubmed: 37240385
pii: ijms24109038
doi: 10.3390/ijms24109038
pmc: PMC10218876
pii:
doi:
Substances chimiques
Interleukin-15
0
Ligands
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : SPARK-program of the Berlin Institute of Health@Charite
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