Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy

Yue Wang, Shi-Kun Zhou, Yan Wang, Zi-Dong Lu, Yue Zhang, Cong-Fei Xu () and Jun Wang ()
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Yue Wang: South China University of Technology, Guangzhou International Campus
Shi-Kun Zhou: South China University of Technology, Guangzhou International Campus
Yan Wang: South China University of Technology
Zi-Dong Lu: South China University of Technology
Yue Zhang: South China University of Technology, Guangzhou International Campus
Cong-Fei Xu: South China University of Technology, Guangzhou International Campus
Jun Wang: South China University of Technology, Guangzhou International Campus

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract PD-1/PD-L1 blockade therapy that eliminates T-cell inhibition signals is successful, but poor benefits are often observed. Increasing T-cell infiltration and quantity of PD-1/PD-L1 inhibitors in tumor can improve efficacy but remains challenging. Here, we devise tumor-specific gene nanomedicines to mobilize tumor cells to secrete CXCL9 (T-cell chemokine) and anti-PD-L1 scFv (αPD-L1, PD-L1 blocking agent) for enhanced immunotherapy. The tyrosinase promoter-driven NPTyr-C9AP can specifically co-express CXCL9 and αPD-L1 in melanoma cells, thereby forming a CXCL9 gradient for T-cell recruitment and high intratumoral αPD-L1 concentration for enhancing T-cell activation. As a result, NPTyr-C9AP shows strong antimelanoma effects. Moreover, specific co-expression of CXCL9 and αPD-L1 in various tumor cells is achieved by replacing the tyrosinase promoter of NPTyr-C9AP with a survivin promoter, which increases T-cell infiltration and activation and therapeutic efficacy in multiple tumors in female mice. This study provides a strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.

Date: 2023
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DOI: 10.1038/s41467-023-37656-w

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