Advanced Science (Oct 2022)

Genetically Engineered Hematopoietic Stem Cells Deliver TGF‐β Inhibitor to Enhance Bone Metastases Immunotherapy

  • Beilei Wang,
  • Jinyu Bai,
  • Bo Tian,
  • Hao Chen,
  • Qianyu Yang,
  • Yitong Chen,
  • Jialu Xu,
  • Yue Zhang,
  • Huaxing Dai,
  • Qingle Ma,
  • Ziying Fei,
  • Heng Wang,
  • Fang Xu,
  • Xiaozhong Zhou,
  • Chao Wang

DOI
https://doi.org/10.1002/advs.202201451
Journal volume & issue
Vol. 9, no. 28
pp. n/a – n/a

Abstract

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Abstract Owing to the immune microenvironment of bones and low selectivity of the drug, patients with bone metastases often respond poorly to immunotherapy. In this study, programmed cell death protein 1 (PD1)‐expressing hematopoietic stem cells (HSCs) are genetically engineered for bone‐targeted delivery of the transforming growth factor beta (TGF‐β) small‐molecule inhibitor SB‐505124 (SB@HSCs‐PD‐1). Intriguingly, compared to anti‐PD‐L1 monoclonal antibodies, as “living drugs”, HSCs‐PD‐1 not only show great targeting ability to the bone marrow, but are also able to reduplicate themselves within the bone marrow niche and continuously express PD‐1 molecules. The SB released from HSCs‐PD‐1 competitively bound to TGF‐β receptors on CD4+ T cells and facilitate CD4+ T cell differentiation to helper T (TH)1 and TH2 cells, thereby reprogramming the local immunosuppressive milieu of the bone marrow. Additionally, HSCs‐PD‐1 can block programmed death‐ligand 1 on tumor and myeloid cells, resulting in reinvigorated anti‐tumor immunity of T cells. In conclusion, in the present study, an alternative cell engineering strategy is delineated for immune checkpoint blockade therapy, to target bone metastasis using HSCs as a platform, which shows great promise in the treatment of bone metastases.

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