Abstract
Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be “armed” with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy.
Original language | English |
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Journal | EMBO Molecular Medicine |
Volume | 16 |
Issue number | 11 |
Pages (from-to) | 2775-2794 |
Number of pages | 20 |
ISSN | 1757-4676 |
DOIs | |
Publication status | Published - 2024 |
Bibliographical note
Publisher Copyright:© The Author(s) 2024.
Keywords
- CAR T Cells
- Chondroitin Sulfate
- Immunotherapy
- Oncofetal CS
- Solid Tumor