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Theranostics 2024; 14(3):1010-1028. doi:10.7150/thno.89144 This issue Cite

Research Paper

Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses

Chengyan Zhang^1,*, Xi Nan^2,*, Bei Zhang^2,*, Hao Wu^3,*, Xianchang Zeng², Zhengbo Song⁴, Shumin Li⁵, Jiaoli Wang^6,7, Shaofang Xie⁸, Gensheng Zhang⁹, Huiqing Xiu², Jianli Wang^10,11, Jufeng Guo¹², Pingli Wang^5✉, Zhijian Cai^2✉, Yunfang Zhen^13✉, Yingying Shen^1✉

1. Laboratory of Cancer Biology, Key lab of Biotherapy in Zhejiang, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang 310020, China.
2. Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, China.
3. Gastroenterology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325000 Wenzhou, China.
4. Department of Medical Oncology, Zhejiang Cancer Hospital, 310022 Hangzhou, China.
5. Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, 310003 Hangzhou, China.
6. Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 310006 Hangzhou, China.
7. Zhejiang University Cancer Centre, 310006 Hangzhou, China.
8. School of Life Science, Westlake University, 310024 Hangzhou, China.
9. Department of Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China.
10. Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, China.
11. Institute of Hematology Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, 310006 Hangzhou, China.
12. Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School Of Medicine, Westlake University, 310006, Hangzhou, China.
13. Department of Orthopaedics, Children's Hospital of Soochow University, 215002 Suzhou, China.
*These authors contributed equally.

✉ Corresponding authors: w_pl77com; caizjedu.cn; yfzhenedu.cn; syy714edu.cn.

Abstract

Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered.

Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53^fl/flLSL-Kras^G12D, Ccr7^-/-, Cd93^-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed.

Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93.

Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.

Keywords: CD93, Anti-CD93, Lung tumors, Pleural mesothelial cells, Extracellular vesicles, CCL21

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