<br>使用 CD44 靶向配体对自然杀伤细胞进行表面工程，用于增强癌症免疫治疗,Small

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使用 CD44 靶向配体对自然杀伤细胞进行表面工程，用于增强癌症免疫治疗
Small ( IF 13.0 ) Pub Date : 2023-12-31 , DOI: 10.1002/smll.202306738
Sungjun Kim ₁ , Shujin Li ₂ , Ashok Kumar Jangid ₁ , Hee Won Park ₁ , Dong-Joon Lee _{2,

3} , Han-Sung Jung ₂ , Kyobum Kim ₁

Affiliation

利用自然杀伤（NK）细胞的过继免疫疗法在治疗血液恶性肿瘤方面已显示出显着的疗效。然而，其对实体瘤的临床干预受到肿瘤特异性抗原表达有限的阻碍。在此，开发了用于 NK 细胞简单离体表面涂层的脂质-PEG 缀合透明质酸 (HA) 材料 (HA-PEG-Lipid)，用于 1) 通过疏水相互作用进行脂质介导的细胞膜锚定，从而 2) 充分呈现将 CD44 配体（即 HA）转移到 NK 细胞上以进行癌症靶向，无需进行基因操作。膜工程NK细胞可以通过HA-CD44亲和力选择性识别CD44过表达的癌细胞，随后诱导NK细胞原位激活以消除癌症。因此，使用HA-PEG-Lipid的表面工程NK细胞（HANK细胞）与CD44过表达的MIA PaCa-2胰腺癌细胞建立免疫突触，触发“识别-激活”机制，最终消灭癌细胞。此外，在小鼠异种移植肿瘤模型中，与 NK 细胞和吉西他滨相比，施用的 HANK 细胞显示出对实体瘤的显着浸润，导致肿瘤凋亡/坏死，并有效抑制肿瘤进展和转移。总而言之，HA-PEG-Lipid 生物材料通过促进表面工程 HANK 细胞的顺序识别激活机制，加速了实体瘤的治疗，这为 NK 细胞介导的免疫治疗提供了一种有前景的方法。

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Surface Engineering of Natural Killer Cells with CD44-targeting Ligands for Augmented Cancer Immunotherapy

Adoptive immunotherapy utilizing natural killer (NK) cells has demonstrated remarkable efficacy in treating hematologic malignancies. However, its clinical intervention for solid tumors is hindered by the limited expression of tumor-specific antigens. Herein, lipid-PEG conjugated hyaluronic acid (HA) materials (HA-PEG-Lipid) for the simple ex-vivo surface coating of NK cells is developed for 1) lipid-mediated cellular membrane anchoring via hydrophobic interaction and thereby 2) sufficient presentation of the CD44 ligand (i.e., HA) onto NK cells for cancer targeting, without the need for genetic manipulation. Membrane-engineered NK cells can selectively recognize CD44-overexpressing cancer cells through HA-CD44 affinity and subsequently induce in situ activation of NK cells for cancer elimination. Therefore, the surface-engineered NK cells using HA-PEG-Lipid (HANK cells) establish an immune synapse with CD44-overexpressing MIA PaCa-2 pancreatic cancer cells, triggering the “recognition-activation” mechanism, and ultimately eliminating cancer cells. Moreover, in mouse xenograft tumor models, administrated HANK cells demonstrate significant infiltration into solid tumors, resulting in tumor apoptosis/necrosis and effective suppression of tumor progression and metastasis, as compared to NK cells and gemcitabine. Taken together, the HA-PEG-Lipid biomaterials expedite the treatment of solid tumors by facilitating a sequential recognition-activation mechanism of surface-engineered HANK cells, suggesting a promising approach for NK cell-mediated immunotherapy.

更新日期：2023-12-31

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