摘要
Combination therapy with checkpoint inhibitors blocks inhibitory immune cell signaling and improves clinical responses to anticancer treatments.However,continued development of innovative and controllable delivery systems for immune-stimulating agents is necessary to optimize clinical responses.Herein,we engineered Salmonella to deliver recombinant granulocyte macrophage colony stimulating factor(GM-CSF)in a controllable manner for combination treatment with a programmed death-ligand 1(PD-L1)inhibitor.The engineered Salmonella enabled delivery of recombinant GM-CSF into mouse tumors,activating recruitment of immune cells,such as M1-polarized macrophages,dendritic cells,and CD8^(+)T cells.Combination treatment with the PD-L1 inhibitor and engineered Salmonella increased the survival rate of tumor-bearing mice by 25%.New tumor growth was strongly suppressed,and visible tumors disappeared at 120 days post-infection(dpi)in mice rechallenged with additional tumor implantation at 100 dpi.The number of memory T cells increased>2-fold in tumor-rechallenged mice.Our findings demonstrate superiority of the engineered Salmonella as a cancer therapeutic agent with pre-cise targeting ability,immune-boosting activity,and ease of combination with other therapeutics.
基金
supported by National Research Foundation of Korea grants funded by the Korean government(NRF-2022R1A2 C1009875,NRF-2017R1A5A2015385,and NRF-2018M3A9H3023081,Korea)
by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health and Welfare,Republic of Korea(HR20C0025)
Heung Jin Jeon was supported by NRF-2020R1A6A3A01099531(Korea)
Daejin Lim was supported by NRF-RS-2023-00210053(Korea)
Jae-Ho Jeong was supported by NRF-2020R1A5A2031185(Korea).Miryoung Song was supported by NRF-2022M3E5F1018375,2019M3E5D5066666 and the Hankuk University of Foreign Studies Research Fund of 2024(Korea).
