嵌合抗原受体树突状细胞靶向输送单一杀瘤因子用于癌症免疫疗法。

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-08-06 DOI:10.1007/s00262-024-03788-1
Rong Duan, Philip Milton, Chutamath Sittplangkoon, Xin Liu, Zhining Sui, Brendan F Boyce, Zhenqiang Yao
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引用次数: 0

摘要

背景:嵌合抗原受体(CAR)-T 细胞可产生多种细胞因子,用于治疗血癌。然而,它们在治疗实体瘤方面效果不佳,而且会导致严重的副作用,包括细胞因子释放综合征。TNFα 是一种杀伤肿瘤的细胞因子,但它会显著增加 cIAP1 和 cIAP2 的蛋白水平,cIAP1 和 cIAP2 是 E3 泛素连接酶凋亡抑制蛋白(IAP)家族的成员,可限制 Caspase 诱导的细胞凋亡。IAP 拮抗剂降解 IAP 蛋白并不能有效杀死癌细胞,却能使 TNFα 强力诱导癌细胞凋亡。方法:设计人树突状细胞(DCs),使其表达单一杀瘤因子 TNFα,并表达膜锚定 Mucin1 抗体 scFv,命名为 Mucin 1 定向表达 TNFα 的 DCs(M-DCsTNF)。研究人员在体外和体内测试了 M-DCsTNF 识别和治疗乳腺癌的功效:结果:Mucin1 在多种人类乳腺癌细胞系表面高度表达。M-DCsTNF可直接与NSG小鼠骨中的MDA-MB-231细胞结合。M-DCsTNF 加上 IAP 拮抗剂 SM-164,但两者都不能单独诱导 MDA-MB-231 乳腺癌细胞凋亡,而 TNF 抗体能阻止这种凋亡。重要的是,M-DCsTNF 联合 SM-164(而非单独 SM-164)可抑制患者来源的乳腺癌在 NSG 小鼠体内的生长:结论:TNFα与IAP拮抗剂结合的收养细胞靶向递送是治疗乳腺癌的一种新的有效方法,并可扩展到治疗其他实体癌。与 CAR-T 细胞不同的是,除了额外过表达的 TNF 外,这种新型收养细胞不会被激活以产生多种细胞因子,因此可以避免细胞因子释放综合征等严重副作用。
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Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy.

Background: Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.

Methods: Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF). The efficacy of M-DCsTNF in recognizing and treating breast cancer was tested in vitro and in vivo.

Results: Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.

Conclusion: An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.

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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
期刊最新文献
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