Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors

Yukun Huang, Yu Chen, Songlei Zhou, Liang Chen, Jiahao Wang, Yuanyuan Pei, Minjun Xu, Jingxian Feng, Tianze Jiang, Kaifan Liang, Shanshan Liu, Qingxiang Song, Gan Jiang, Xiao Gu, Qian Zhang, Xiaoling Gao () and Jun Chen ()
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Yukun Huang: Fudan University
Yu Chen: Fudan University
Songlei Zhou: Fudan University
Liang Chen: Fudan University
Jiahao Wang: Fudan University
Yuanyuan Pei: Fudan University
Minjun Xu: Fudan University
Jingxian Feng: Fudan University
Tianze Jiang: Fudan University
Kaifan Liang: Fudan University
Shanshan Liu: Fudan University
Qingxiang Song: Shanghai Jiao Tong University School of Medicine
Gan Jiang: Shanghai Jiao Tong University School of Medicine
Xiao Gu: Shanghai Jiao Tong University School of Medicine
Qian Zhang: Shanghai Jiao Tong University School of Medicine
Xiaoling Gao: Shanghai Jiao Tong University School of Medicine
Jun Chen: Fudan University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The failure of immunotherapies in immune-excluded tumor (IET) is largely ascribed to the void of intratumoral cytotoxic T cells (CTLs). The major obstacles are the excessive stroma, defective vasculatures and the deficiency of signals recruiting CTLs. Here we report a dual-mechanism based CTLs infiltration enhancer, Nano-sapper, which can simultaneously reduce the physical obstacles in tumor microenvironment and recruiting CTLs to potentiate immunotherapy in IET. Nano-sapper consists a core that co-loaded with antifibrotic phosphates-modified α-mangostin and plasmid encoding immune-enhanced cytokine LIGHT. Through reversing the abnormal activated fibroblasts, decreasing collagen deposition, normalizing the intratumoral vasculatures, and in situ stimulating the lymphocyte-recruiting chemoattractants expression, Nano-sapper paves the road for the CTLs infiltration, induces the intratumoral tertiary lymphoid structures, thus reshapes tumor microenvironment and potentiates checkpoint inhibitor against IET. This study demonstrates that the combination of antifibrotic agent and immune-enhanced cytokine might represent a modality in promoting immunotherapy against IET.

Date: 2020
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DOI: 10.1038/s41467-020-14425-7

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