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  2. Nano-chemical priming strategy to enhance TGF-β resistance and anti-tumor activity of natural killer cells

Nano-chemical priming strategy to enhance TGF-β resistance and anti-tumor activity of natural killer cells

  • J Control Release. 2024 Feb 13:367:768-778. doi: 10.1016/j.jconrel.2024.02.008.
Seung Hee Choi 1 Hui Bang Cho 1 Jin-Ho Choi 1 Hye Jin Kim 1 Hye Jung Jang 1 Seohyun Cho 1 Eunchong Maeng 1 Hail Park 1 Ki Seo Ryu 1 Keun-Hong Park 2 Kyung-Soon Park 3
Affiliations

Affiliations

  • 1 Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea.
  • 2 Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea. Electronic address: pkh0410@cha.ac.kr.
  • 3 Department of Biomedical Science, CHA University, Seongnam-si, Republic of Korea. Electronic address: kspark@cha.ac.kr.
Abstract

Immunotherapy based on adoptive transfer of natural killer (NK) cells is a promising strategy for circumventing the limitations of Cancer treatments. However, components of the immunosuppressive tumor microenvironment (TME), such as transforming growth factor-beta (TGF-β), compromise the therapeutic efficacy of NK cells significantly. To address these limitations, we developed a novel method of engineering NK cells for adaptive transfer. The method is based on nanogels that serve two functions: (1) they overcome the TGF-β-mediated stress environment of the TME, and (2) they enhance the direct anti-tumor activity of NK cells. Previously, we demonstrated that cationic compounds such as 25 K branched polyethylenimine (25 K bPEI) prime NK cells, putting them in a 'ready-to-fight' state. Based on these findings, we designed nanogels that have two primary characteristics: (1) they encapsulate galunisertib (Gal), which is used clinically to inhibit TGF-β Receptor activity, thereby blocking TGF-β signaling; and (2) they provide cells with a surface coating of 25 K bPEI. When grown in culture medium containing TGF-β, nanogel-treated NK cells demonstrated greater migration ability, degranulation activity, and cytotoxicity towards Cancer cells than untreated NK cells. Additionally, the in vivo efficacy of nanogel-treated NK cells against PC-3 xenografts was significantly greater than that of Chem_NK cells primed by 25 K bPEI alone. These findings suggest that Gal-loaded 25 K bPEI-coated nanogels exert anti-tumor effects via chemical priming, as well suppressing the effects of TGF-β on NK cells. We also expect 25 K bPEI-based nanogels to have great potential to overcome the suppressive effects of the TME through their NK cell-priming activity and delivery of the desired chemicals.

Keywords

Immunotherapy; Natural killer (NK) cells; Transforming growth factor-beta (TGF-β); Tumor microenvironment (TME).

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