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Theranostics 2024; 14(7):2757-2776. doi:10.7150/thno.94537 This issue Cite

Research Paper

Targeting tumor cell-to-macrophage communication by blocking Vtn-C1qbp interaction inhibits tumor progression via enhancing macrophage phagocytosis

Chen Zhang^1,2#, Yi Liu^1#, Jiayu Jiang^2,3, Chong Chen^2,3, Zhaojun Duan^2,3, Huifang Su^2,3, Shijian Wang¹, Baorui Tian¹, Yi Shi¹, Rong Xiang^1✉, Yunping Luo^2,3✉

1. The School of Medicine, College of Pharmacy, Nankai University, Tianjin 300071, China.
2. Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
3. Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy, Changzhou 213149, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Yunping Luo, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing 100005, China, ypluopumc.edu.cn. Rong Xiang, The School of Medicine, College of Pharmacy, Nankai University, Tianjin 300071, China, rxiangedu.cn. More

Abstract

Background: Cancer cells are capable of evading clearance by macrophages through overexpression of anti-phagocytic surface proteins known as "don't eat me" signals. Monoclonal antibodies that antagonize the "don't-eat-me" signaling in macrophages and tumor cells by targeting phagocytic checkpoints have shown therapeutic promises in several cancer types. However, studies on the responses to these drugs have revealed the existence of other unknown "don't eat me" signals. Moreover, identification of key molecules and interactions regulating macrophage phagocytosis is required for tumor therapy.

Methods: CRISPR screen was used to identify genes that impede macrophage phagocytosis. To explore the function of Vtn and C1qbp in phagocytosis, knockdown and subsequent functional experiments were conducted. Flow cytometry were performed to explore the phagocytosis rate, polarization of macrophage, and immune microenvironment of mouse tumor. To explore the underlying molecular mechanisms, RNA sequencing, immunoprecipitation, mass spectrometry, and immunofluorescence were conducted. Then, in vivo experiments in mouse models were conducted to explore the probability of Vtn knockdown combined with anti-CD47 therapy in breast cancer. Single-cell sequencing data from the Gene Expression Omnibus from The Cancer Genome Atlas database were analyzed.

Results: We performed a genome-wide CRISPR screen to identify genes that impede macrophage phagocytosis, followed by analysis of cell-to-cell interaction databases. We identified a ligand-receptor pair of Vitronectin (Vtn) and complement C1Q binding protein (C1qbp) in tumor cells or macrophages, respectively. We demonstrated tumor cell-secreted Vtn interacts with C1qbp localized on the cell surface of tumor-associated macrophages, inhibiting phagocytosis of tumor cells and shifting macrophages towards the M2-like subtype in the tumor microenvironment. Mechanistically, the Vtn-C1qbp axis facilitated FcγRIIIA/CD16-induced Shp1 recruitment, which reduced the phosphorylation of Syk. Furthermore, the combination of Vtn knockdown and anti-CD47 antibody effectively enhanced phagocytosis and infiltration of macrophages, resulting in a reduction of tumor growth in vivo.

Conclusions: This work has revealed that the Vtn-C1qbp axis is a new anti-phagocytic signal in tumors, and targeting Vtn and its interaction with C1qbp may sensitize cancer to immunotherapy, providing a new molecular target for the treatment of triple-negative breast cancer.

Keywords: Breast cancer, CRISPR screen, Vtn-C1qbp, macrophage, phagocytosis

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