Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release.

Abstract

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).

• Authors: Shu Lian, Ruizhi Xie, Yuying Ye, Xiaodong Xie, Shuhui Li, Yusheng Lu, Bifei Li, Yunlong Cheng, Vladimir L Katanaev, Lee Jia
• Journal: EBioMedicine (EBioMedicine) Vol. 42 Pg. 281-295 (Apr 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30878596 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• B7-H1 Antigen
• Biomarkers
• CD274 protein, human
• CD47 Antigen
• CD47 protein, human
• Cytokines

Topics

• Adaptive Immunity
• B7-H1 Antigen (metabolism)
• Biomarkers
• CD47 Antigen (metabolism)
• Cytokines (metabolism)
• Cytotoxicity, Immunologic
• Humans
• Immunity, Innate
• Immunohistochemistry
• Neoplasms (immunology, metabolism, pathology)
• T-Lymphocytes (immunology, metabolism)