对H2O2和缺氧具有耐受性的工程CAR-NK细胞可抑制三阴性乳腺癌术后复发。

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Yan Liu, Jiahui Chen, Jia Tian, Yu Hao, Xinxing Ma, Yehui Zhou, Liangzhu Feng
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引用次数: 0

摘要

手术切除是三阴性乳腺癌(TNBC)患者的主要治疗方法,但术后局部复发和转移复发率较高。虽然嵌合抗原受体工程化的自然杀伤(CAR-NK)细胞疗法能特异性识别和消灭肿瘤细胞,但其对TNBC的治疗效力却因恶劣的肿瘤微环境而受到明显抑制,这限制了CAR-NK细胞在肿瘤块内的浸润、存活和效应功能。在这里,HER1表达的TNBC靶向CAR-NK(HER1-CAR-NK)细胞经基因工程与过氧化氢酶结合,通过催化肿瘤内主要活性氧--过氧化氢分解为氧气,使它们对TNBC肿瘤内的高水平氧化应激和缺氧具有耐受性。我们将这些细胞称为 HER1-CAR-CAT-NK 细胞。用可注射的藻酸盐水凝胶进行瘤内固定后,HER1-CAR-CAT-NK细胞能持续减轻肿瘤缺氧,并在TNBC肿瘤内表现出明显增强的持久性和效应功能。因此,局部 HER1-CAR-CAT-NK 细胞疗法不仅能抑制局部原发性残留肿瘤的生长,还能激发全身抗肿瘤活性,抑制远处肿瘤的生长。这项研究强调,带有过氧化氢酶的HER1-CAR-NK细胞基因工程是抑制TNBC肿瘤术后局部和远处复发的一种有前途的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Engineered CAR-NK Cells with Tolerance to H2O2 and Hypoxia Can Suppress Postoperative Relapse of Triple-Negative Breast Cancers.

Surgical resection is a primary treatment option for patients with triple-negative breast cancer (TNBC), but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor-engineered NK (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival, and effector functions of CAR-NK cells inside tumor masses. In this study, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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