Targeting glycosylated antigens on cancer cells using siglec-7/9-based CAR T-cells.
Animals
Antigens, CD
/ metabolism
Antigens, Differentiation, Myelomonocytic
/ metabolism
Cell Line
Cell Line, Tumor
Glycosylation
HEK293 Cells
HeLa Cells
Heterografts
/ metabolism
Humans
Jurkat Cells
K562 Cells
Lectins
/ metabolism
Leukocytes, Mononuclear
/ metabolism
Mice
Mice, Inbred NOD
Mice, SCID
Receptors, Antigen, T-Cell
/ metabolism
Sialic Acid Binding Immunoglobulin-like Lectins
/ metabolism
T-Lymphocytes
/ metabolism
T-cell engineering
chimeric receptors
sialylation
tumor immunotherapy
Journal
Molecular carcinogenesis
ISSN: 1098-2744
Titre abrégé: Mol Carcinog
Pays: United States
ID NLM: 8811105
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
12
02
2020
revised:
29
04
2020
accepted:
30
04
2020
pubmed:
12
5
2020
medline:
9
9
2020
entrez:
12
5
2020
Statut:
ppublish
Résumé
Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach. Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.
Substances chimiques
Antigens, CD
0
Antigens, Differentiation, Myelomonocytic
0
Lectins
0
Receptors, Antigen, T-Cell
0
SIGLEC7 protein, human
0
SIGLEC9 protein, human
0
Sialic Acid Binding Immunoglobulin-like Lectins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
713-723Informations de copyright
© 2020 Wiley Periodicals LLC.
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