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新型融合蛋白蜂毒素-MIL-2 在肺腺癌细胞 A549 中表现出强烈的抗肿瘤免疫效应。

The Novel Fusion Protein Melittin-MIL-2 Exhibits Strong Antitumor Immune Effect in Lung Adenocarcinoma Cell A549.

机构信息

Department of Clinical Laboratory, Key Laboratory of Laboratory Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.

出版信息

Clin Respir J. 2024 Jul;18(7):e13805. doi: 10.1111/crj.13805.

DOI:10.1111/crj.13805
PMID:39003635
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11246609/
Abstract

In previous studies, we developed a novel fusion protein named "melittin-MIL-2" which exhibited more anti-tumor activity. However, it remains unclear whether melittin-MIL-2 possesses antitumor immune effect on lung adenocarcinoma. In this study, the immune effect and mechanism of melittin-MIL-2 inhibiting the growth and invasion of lung adenocarcinoma will be investigated, in order to provide novel perspectives for the immunotherapy of lung cancer. The results indicated that melittin-MIL-2 promoted T cell proliferation, enhanced NK cell cytotoxicity, and boosted IFN-γ secretion in PBMCs. After melittin-MIL-2 stimulation, perforin expression and LAK/NK-like killing activities of human PBMCs and NK cells were significantly enhanced. Melittin-MIL-2 is capable of hampering the development and proliferation of lung adenocarcinoma cell A549. ICAM-1 and Fas expression in A549 cells exposed to melittin-MIL-2 rose significantly. The expression levels of TLR8 and VEGF in A549 cells decreased significantly after melittin-MIL-2 stimulation. In vivo, melittin-MIL-2 substantially impeded the growth of lung adenocarcinoma and formed an immune-stimulating microenvironment locally in tumor tissues. In conclusion, the novel fusion protein melittin-MIL-2 exhibits strong anti-tumor immune effect in lung adenocarcinoma cell A549 via activating the LFA-1/ICAM-1 and Fas/FasL pathways to enhance cytolytic activity, upregulating the secretion of IFN-γ and perforin, and boosting LAK/NK-like killing activities. Immuno-effector cells and their secreted cytokines can form immune stimulation microenvironment locally in lung adenocarcinoma Lewis mice tissue.

摘要

在之前的研究中，我们开发了一种名为“蜂毒素-MIL-2”的新型融合蛋白，它表现出更强的抗肿瘤活性。然而，蜂毒素-MIL-2 是否对肺腺癌具有抗肿瘤免疫作用尚不清楚。本研究旨在探讨蜂毒素-MIL-2 抑制肺腺癌细胞生长和侵袭的免疫作用及其机制，为肺癌的免疫治疗提供新的思路。结果表明，蜂毒素-MIL-2 可促进 T 细胞增殖，增强 NK 细胞的细胞毒性，并促进 PBMCs 中 IFN-γ 的分泌。经蜂毒素-MIL-2 刺激后，人 PBMCs 和 NK 细胞的穿孔素表达和 LAK/NK 样杀伤活性显著增强。蜂毒素-MIL-2 能够抑制肺腺癌细胞 A549 的发展和增殖。暴露于蜂毒素-MIL-2 的 A549 细胞中 ICAM-1 和 Fas 的表达显著增加。蜂毒素-MIL-2 刺激后 A549 细胞中 TLR8 和 VEGF 的表达水平显著降低。在体内，蜂毒素-MIL-2 可显著抑制肺腺癌的生长，并在肿瘤组织局部形成免疫刺激微环境。综上所述，新型融合蛋白蜂毒素-MIL-2 通过激活 LFA-1/ICAM-1 和 Fas/FasL 通路增强细胞毒性，上调 IFN-γ 和穿孔素的分泌，增强 LAK/NK 样杀伤活性，从而在肺腺癌细胞 A549 中表现出强烈的抗肿瘤免疫作用。免疫效应细胞及其分泌的细胞因子可在肺腺癌 Lewis 小鼠组织局部形成免疫刺激微环境。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/bf4c91d68b33/CRJ-18-e13805-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/dc1fbbc8b4d3/CRJ-18-e13805-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/c399b9259dfb/CRJ-18-e13805-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/2e07ba3af2d5/CRJ-18-e13805-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/53bcd7b92852/CRJ-18-e13805-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/6796ac0ab996/CRJ-18-e13805-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/127164f15761/CRJ-18-e13805-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/bf4c91d68b33/CRJ-18-e13805-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/dc1fbbc8b4d3/CRJ-18-e13805-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/c399b9259dfb/CRJ-18-e13805-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/2e07ba3af2d5/CRJ-18-e13805-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/53bcd7b92852/CRJ-18-e13805-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/6796ac0ab996/CRJ-18-e13805-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/127164f15761/CRJ-18-e13805-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/571b/11246609/bf4c91d68b33/CRJ-18-e13805-g002.jpg

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