Modifying T cells to attack tumors using engineered chimeric receptors display powerful new therapeutic capabilities. Unfortunately, the effectiveness of therapeutic T cells is limited due to the inherent T cell responses: certain facets of endogenous response programs may be toxic, and the ability to overcome the immunosuppression in TME is deficient. Here we developed a Notch receptor based synNotch T cell platform that is able to response to target tumor cells and selectively lead to CXCL10 production. Further study showed that the administration of synNotch T cells significantly inhibited the tumor growth in a humanized murine model, accompanied by the increased infiltration of CD3+T cells and elevated level of CXCL10 and IFN-γ in the tumor site. A slightly increased level of CXCL10 and limited IFN-γ were found in the serum in mice received synNotch T cells, suggesting a high security of this treatment. Finally, we demonstrated that CXCL10 is sufficient and indispensable for the synNotch T cells induced anti-tumor effect. This study provided theoretical and experimental bases for the clinical implication of CXCL10 encoding synNotch T cells.
Keywords: Adoptive T cell therapy; CXCL10; Cytokine storm; Engineered chimeric receptors; synNotch T cells.
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