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

• Published in: Nature communications Vol. 11; no. 1; p. 622
• Main Authors: Huang, Yukun, Chen, Yu, Zhou, Songlei, Chen, Liang, Wang, Jiahao, Pei, Yuanyuan, Xu, Minjun, Feng, Jingxian, Jiang, Tianze, Liang, Kaifan, Liu, Shanshan, Song, Qingxiang, Jiang, Gan, Gu, Xiao, Zhang, Qian, Gao, Xiaoling, Chen, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-01-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/19; 14/34; 14/35; 14/63; 140/131; 140/58; 147/28; 38/77; 38/88; 631/67/1059; 631/67/327; 631/67/580; 639/925/352; 82/51; 82/80; Animals; Barriers; Chemotactic factors; Collagen; Cytokines; Cytokines - metabolism; Cytotoxicity; Disease Models, Animal; Fibroblasts; Fibrosis; Humanities and Social Sciences; Immune checkpoint; Immunotherapy; Infiltration; Lymphocytes; Lymphocytes T; Male; Metastases; Mice; Mice, Inbred C57BL; multidisciplinary; Nanomedicine - methods; Neoplasms - blood supply; Neoplasms - immunology; Neoplasms - therapy; NIH 3T3 Cells; Normalizing; Pancreatic cancer; Phosphates; Programmed Cell Death 1 Receptor; Science; Science (multidisciplinary); Stroma; T-Lymphocytes, Cytotoxic - metabolism; Tumor Microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14425-7

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.
The exclusion of cytotoxic T cells remains an important barrier to the efficacy of immunotherapies. Here the authors demonstrate that the combination anti-fibrosis agents and immune-enhanced cytokines can enhance T cell infiltration in a mouse model of pancreatic cancer.