过氧化氢酶保护CAR-T细胞以及氧化应激导致的抗肿瘤活性丢失的旁临T细胞

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Coexpressed Catalase Protects Chimeric Antigen Receptor-Redirected T Cells as well as Bystander Cells from Oxidative Stress-Induced Loss of Antitumor Activity.

Abstract

Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3ζ chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress-mediated repression.

过氧化氢酶保护CAR-T细胞以及氧化应激导致的抗肿瘤活性丢失的旁临T细胞

摘要

利用过继T细胞治疗技术治疗癌症病人已经有了良好的效果。然而，在实体肿瘤中，T细胞进入了一个充满敌意的环境，特别是随着肿瘤周围环境的一个标志炎症活动的增加，伴随着丰富的活性氧（ROS），大大降低了抗肿瘤活性。我们开发了一个策略，能够使得T细胞应对ROS时重新恢复活性，通过共表达过氧化氢酶和嵌合抗原受体来增加代谢H2O2的抗氧化能力。事实上，使用双表达载体修饰T细胞，同时表达过氧化氢酶和表达CA的过氧化氢酶（CAR-CAT），与CAR-T细胞相比具有更好的优势，不管是在基础状态还是保持其抗肿瘤活性，这类细胞内过氧化氢酶会升高，它们能够减少ROS的积累，降低氧化状态。此外，即使在高浓度的H2O2的存在下，CAR-CAT细胞能够产生大量的未转染的表达CD3ζ链的免疫效应细胞来作为保护。具有ROS敏感的旁临NK细胞，与CAR-CAT细胞混合后，在H2O2诱导的氧化应激环境中能够有效地消除K562靶细胞。这种方法代表了一个新的手段，用于保护肿瘤浸润细胞，避免肿瘤相关的氧化应激导致的抑制。

出自爱康得生物技术