肿瘤细胞治疗研究
英文原题：PD‑L1 deficient exosomes derived from lung cancer cell line enhances NK cell‑mediated anti‑tumor immunity against lung cancer.
作为固有免疫细胞，NK细胞在对抗肿瘤和感染中发挥重要作用，使其成为癌症免疫治疗的有前景的工具。
作为固有免疫细胞，NK 细胞在对抗肿瘤和感染中发挥重要作用，使其成为肿瘤免疫治疗中颇具前景的工具。尽管 NK 细胞在血液系统恶性肿瘤治疗中取得了令人瞩目的成果，但 NK 细胞对实体瘤的治疗效率仍不理想。通过增强 NK 细胞对特定靶细胞的敏感性，有可能提升其对实体瘤的细胞毒性和治疗效果。肿瘤来源外泌体（TEXs）对 NK 细胞具有免疫刺激作用，然而，TEXs 携带的免疫检查点配体也会损害 NK 细胞的活性。在本研究中，从肺癌细胞系 A549 中敲除 PD-L1，并使用来源于野生型 A549 细胞的外泌体（WT-EXO）和 PD-L1 敲除 A549 细胞的外泌体（KO-EXO）预免疫 NK 细胞。结果表明，敲除 PD-L1 可降低 WT-EXO 对 NK 细胞活力的抑制作用。同时，A549 细胞来源外泌体（WT-EXO 和 KO-EXO）均能增强 NK 细胞的细胞毒性，其中 KO-EXO 表现出比另一种更好的刺激效果。NK 细胞杀伤率的增强可部分归因于外泌体预免疫后 IFN-γ 分泌增加。Western blot 结果表明，信号蛋白 pSTAT1 及其相关通路在外泌体诱导的 NK 细胞细胞毒性增强中发挥重要作用。同时，观察到外泌体预免疫的 NK 细胞中免疫记忆标志物 CD25 和 CD159c 上调。此外，在 A549 细胞荷瘤小鼠模型中，与未处理的 NK 细胞相比，KO-EXO 预免疫的 NK 细胞表现出更好的浸润和抗肿瘤效果。这些结果凸显了工程化 TEXs 在促进基于 NK 细胞的抗肺癌免疫治疗中的治疗潜力。
As innate immune cells, natural killer (NK) cells play a vital role in combating tumors and infections, making them a promising tool for cancer immunotherapy. Although NK cell has achieved impressive results in treating of hematologic malignancies, the therapeutic efficiency of NK cells on solid tumors remains unsatisfactory. By enhancing the sensitivity of NK cells to specific target cells, it is possible to boost their cytotoxicity and therapeutic effect against solid tumors. Tumor derived exosomes (TEXs) have immunostimulatory effects on NK cells, however, the TEXs carried immune checkpoints ligand also impair NK cells activity. In the present study, PD-L1 was knocked out from lung cancer cell line A549, and the exosomes derived from wild-type A549 cells (WT-EXO) and PD-L1 knocked-out A549 cell (KO-EXO) were used to pre-immunize NK cells. Results showed that, PD-L1 knocking out can reduce the inhibitory effect of WT-EXO on NK cells viability. Meanwhile, A549 cells derived exosomes (WT-EXO and KO-EXO) both boost the cytotoxicity of NK cells, with KO-EXO exhibited better stimulated effect than the other one. The enhanced killing rates of NK cells can be partially attributed to increased IFN-γ secretion following exosomes pre-immunization. Western blot results indicated that the signaling proteins pSTAT1, along with their associated pathways, play important roles in exosomes-induced enhancement of NK cell cytotoxicity. Simultaneously, it was observed that exosomes-preimmunized NK cells exhibited an upregulation of immunological memory markers CD25 and CD159c. Moreover, KO-EXO pre-immunized NK cells showed better infiltration and anti-tumor effects compared to the untreated NK cells in A549 cell bearing mice model. These results highlight the therapeutic potential of engineered TEXs in boosting NK cell based anti-lung cancer immunotherapy.
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