Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2023 Jan 26

PMID 36698296

Authors

Lisen Lu

Huaduan Zi

Jie Zhou

Jing Huang

Zihan Deng

Zijian Tang

Li Li

Xiujuan Shi

Pui-Chi Lo

Jonathan F Lovell

Deqiang Deng

Chao Wan

Honglin Jin

Affiliations

Soon will be listed here.

Abstract

Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.

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References

Gao Y, Zheng X, Chang B, Lin Y, Huang X, Wang W . Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity. Cell Res. 2022; 32(12):1086-1104. PMC: 9715632. DOI: 10.1038/s41422-022-00731-w. View

Gutmann D, Kettenmann H . Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology. Neuron. 2019; 104(3):442-449. PMC: 7288606. DOI: 10.1016/j.neuron.2019.08.028. View

Xie F, Zhou X, Fang M, Li H, Su P, Tu Y . Extracellular Vesicles in Cancer Immune Microenvironment and Cancer Immunotherapy. Adv Sci (Weinh). 2019; 6(24):1901779. PMC: 6918121. DOI: 10.1002/advs.201901779. View

Huang Q, Wu X, Wang Z, Chen X, Wang L, Lu Y . The primordial differentiation of tumor-specific memory CD8 T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell. 2022; 185(22):4049-4066.e25. DOI: 10.1016/j.cell.2022.09.020. View

Li S, Shao L, Xu T, Jiang X, Yang G, Dong L . An indispensable tool: Exosomes play a role in therapy for radiation damage. Biomed Pharmacother. 2021; 137:111401. DOI: 10.1016/j.biopha.2021.111401. View

Zhai D, Huang J, Hu Y, Wan C, Sun Y, Meng J . Ionizing Radiation-Induced Tumor Cell-Derived Microparticles Prevent Lung Metastasis by Remodeling the Pulmonary Immune Microenvironment. Int J Radiat Oncol Biol Phys. 2022; 114(3):502-515. DOI: 10.1016/j.ijrobp.2022.06.092. View

Huang L, Chambliss K, Gao X, Yuhanna I, Behling-Kelly E, Bergaya S . SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature. 2019; 569(7757):565-569. PMC: 6631346. DOI: 10.1038/s41586-019-1140-4. View

Pellerino A, Bruno F, Ruda R, Soffietti R . Systemic Therapy for Lung Cancer Brain Metastases. Curr Treat Options Oncol. 2021; 22(12):110. DOI: 10.1007/s11864-021-00911-7. View

Alahmari A . Blood-Brain Barrier Overview: Structural and Functional Correlation. Neural Plast. 2021; 2021:6564585. PMC: 8668349. DOI: 10.1155/2021/6564585. View

10.

Moller A, Lobb R . The evolving translational potential of small extracellular vesicles in cancer. Nat Rev Cancer. 2020; 20(12):697-709. DOI: 10.1038/s41568-020-00299-w. View

11.

Singh Achrol A, Rennert R, Anders C, Soffietti R, Ahluwalia M, Nayak L . Brain metastases. Nat Rev Dis Primers. 2019; 5(1):5. DOI: 10.1038/s41572-018-0055-y. View

12.

Teng F, Fussenegger M . Shedding Light on Extracellular Vesicle Biogenesis and Bioengineering. Adv Sci (Weinh). 2021; 8(1):2003505. PMC: 7788585. DOI: 10.1002/advs.202003505. View

13.

Kouadir M, Yang L, Tu J, Yin X, Zhou X, Zhao D . Comparison of mRNA expression patterns of class B scavenger receptors in BV2 microglia upon exposure to amyloidogenic fragments of beta-amyloid and prion proteins. DNA Cell Biol. 2011; 30(11):893-7. DOI: 10.1089/dna.2011.1234. View

14.

Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C . Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001; 7(3):297-303. DOI: 10.1038/85438. View

15.

Dai X, Lu L, Deng S, Meng J, Wan C, Huang J . USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer. Theranostics. 2020; 10(20):9332-9347. PMC: 7415808. DOI: 10.7150/thno.47137. View

16.

Engelhardt B, Vajkoczy P, Weller R . The movers and shapers in immune privilege of the CNS. Nat Immunol. 2017; 18(2):123-131. DOI: 10.1038/ni.3666. View

17.

Zhou Y, Peng Z, Seven E, Leblanc R . Crossing the blood-brain barrier with nanoparticles. J Control Release. 2017; 270:290-303. DOI: 10.1016/j.jconrel.2017.12.015. View

18.

Wan C, Sun Y, Tian Y, Lu L, Dai X, Meng J . Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming. Sci Adv. 2020; 6(13):eaay9789. PMC: 7096163. DOI: 10.1126/sciadv.aay9789. View

19.

Fung K, Wang C, Nyegaard S, Heit B, Fairn G, Lee W . SR-BI Mediated Transcytosis of HDL in Brain Microvascular Endothelial Cells Is Independent of Caveolin, Clathrin, and PDZK1. Front Physiol. 2017; 8:841. PMC: 5670330. DOI: 10.3389/fphys.2017.00841. View

20.

Sampson J, Gunn M, Fecci P, Ashley D . Brain immunology and immunotherapy in brain tumours. Nat Rev Cancer. 2019; 20(1):12-25. PMC: 7327710. DOI: 10.1038/s41568-019-0224-7. View