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Targeting glycosylated antigens on cancer cells using siglec‐7/9‐based CAR T‐cells
Author(s) -
Meril Sara,
Harush Ortal,
Reboh Yishai,
Matikhina Tatyana,
Barliya Tilda,
Cohen Cyrille J.
Publication year - 2020
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23213
Subject(s) - biology , siglec , immune system , chimeric antigen receptor , receptor , cancer cell , antigen , microbiology and biotechnology , major histocompatibility complex , immunotherapy , cancer research , immunology , cancer , biochemistry , genetics
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.