Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis

Lang Rao,Guang-Tao Yu,Han Xu,Zijian Zhou,Wenjing Sun,Jingya Guo,Xiaoyuan Chen,Andrew Li,Yang-Xin Fu,Guocan Yu,Anli Zhang,Hong-Gang Xiong,Hongmin Chen,Rui Tian,Zhi-Jun Sun,Kuikun Yang,Zhida Liu,Lei Wu

doi:10.1038/s41467-020-18626-y

Abstract

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a ‘don’t eat me’ signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.

Highlights

Activating macrophages against cancer is promising but challenging
CD47-blocking therapy is the immunosuppressive tumor microenvironment (TME) which is rich in signals that polarize tumorassociated macrophages (TAMs) towards a pro-tumorigenic M2 phenotype[17]
We show that the hNVs, which inherit the capabilities from source cells, can efficiently accumulate in surgical wound sites, interact with circulating tumor cells (CTCs) in the blood, repolarize TAMs towards M1 phenotype, and block the CD47SIRPα interaction (Fig. 1b), accentuating macrophage phagocytosis of cancer cells, as well as potentiating antitumor T cell immunity, while reducing side effects induced by systemic infusion

Summary

Introduction

Activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a ‘don’t eat me’ signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. M2-type macrophages can recruit regulatory T cells (Tregs) and secret anti-inflammatory cytokines which counteract the activation of antitumor T cell immunity by CD47 blocking agents[8,18]. In this context, repolarization of TAMs from a protumorigenic M2 phenotype to an antitumor M1 phenotype may restore efficacy to antitumor immunity of CD47 antagonists. The side effects and limited effectiveness may be caused by nonspecific binding of these CD47 blockades to normal tissues when systemically infused[5,16] It would be ideal for CD47 blocking cancer immunotherapy to focus on the tumor site and avoid interactions in the immune milieu of the other sites. Extracellular vesicles (EVs), including but not limited to exosomes and microvesicles, are lipid vesicles secreted by cells[19]

Methods

Results

Conclusion