Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine releaseResearch in context
Shu Lian,
Ruizhi Xie,
Yuying Ye,
Xiaodong Xie,
Shuhui Li,
Yusheng Lu,
Bifei Li,
Yunlong Cheng,
Vladimir L. Katanaev,
Lee Jia
Affiliations
Shu Lian
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
Ruizhi Xie
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
Yuying Ye
Fujian Provincial People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China
Xiaodong Xie
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
Shuhui Li
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
Yusheng Lu
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China; Marine Drug R&D Center, Institute of Oceangraphy, Minjiang University, Fuzhou 350108, China
Bifei Li
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
Yunlong Cheng
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China
Vladimir L. Katanaev
Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Switzerland; Head of the Natural Products Drug Discovery Laboratory, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
Lee Jia
Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, China; Marine Drug R&D Center, Institute of Oceangraphy, Minjiang University, Fuzhou 350108, China; Corresponding author at: Cancer Metastasis Alert and Prevention Center, Fuzhou University, Sunlight Building, 6FL, Science Park, Xueyuan Road, University Town, Fuzhou 350116, China.
Background: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical “don't find me” signal to the adaptive immune system. Equally CD47 is a critical “don't eat me” signal to the innate immune system and a regulator of the adaptive immune response. Method: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins. Findings: Efficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro. Interpretation: This multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. Fund: This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268). Keywords: CD47/SIPR-α, PD-L1/PD-1, siRNA, Immune therapy, Liposome, Gene therapy, EpCAM targeted
