Cytokine signaling in chimeric antigen receptor T-cell therapy.

IF 4.8 4区 医学 Q2 IMMUNOLOGY International immunology Pub Date : 2024-02-14 DOI:10.1093/intimm/dxad033
Yuki Kagoya
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Abstract

Adoptive immunotherapy using chimeric antigen-receptor (CAR)-engineered T cells can induce robust antitumor responses against hematologic malignancies. However, its efficacy is not durable in the majority of the patients, warranting further improvement of T-cell functions. Cytokine signaling is one of the key cascades regulating T-cell survival and effector functions. In addition to cytokines that use the common γ chain as a receptor subunit, multiple cytokines regulate T-cell functions directly or indirectly. Modulating cytokine signaling in CAR-T cells by genetic engineering is one promising strategy to augment their therapeutic efficacy. These strategies include ectopic expression of cytokines, cytokine receptors, and synthetic molecules that mimic endogenous cytokine signaling. Alternatively, autocrine IL-2 signaling can be augmented through reprogramming of CAR-T cell properties through transcriptional and epigenetic modification. On the other hand, cytokine production by CAR-T cells triggers systemic inflammatory responses, which mainly manifest as adverse events such as cytokine-release syndrome (CRS) and neurotoxicity. In addition to inhibiting direct inflammatory mediators such as IL-6 and IL-1 released from activated macrophages, suppression of T-cell-derived cytokines associated with the priming of macrophages can be accomplished through genetic modification of CAR-T cells. In this review, I will outline recently developed synthetic biology approaches to exploit cytokine signaling to enhance CAR-T cell functions. I will also discuss therapeutic target molecules to prevent or alleviate CAR-T cell-related toxicities.

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嵌合抗原受体 T 细胞疗法中的细胞因子信号转导。
利用嵌合抗原受体(CAR)工程T细胞进行的采纳性免疫疗法可诱导针对血液系统恶性肿瘤的强大抗肿瘤反应。然而,大多数患者的疗效并不持久,因此需要进一步改善T细胞的功能。细胞因子信号转导是调节 T 细胞存活和效应功能的关键级联之一。除了使用共同的 γ 链作为受体亚基的细胞因子外,还有多种细胞因子直接或间接地调节 T 细胞功能。通过基因工程调节 CAR-T 细胞中的细胞因子信号转导是增强其疗效的一种很有前景的策略。这些策略包括异位表达细胞因子、细胞因子受体和模拟内源性细胞因子信号的合成分子。另外,还可以通过转录和表观遗传修饰对 CAR-T 细胞特性进行重编程,从而增强自分泌 IL-2 信号。另一方面,CAR-T 细胞产生的细胞因子会引发全身炎症反应,主要表现为细胞因子释放综合征(CRS)和神经毒性等不良反应。除了抑制活化巨噬细胞释放的 IL-6 和 IL-1 等直接炎症介质外,还可以通过对 CAR-T 细胞进行基因修饰来抑制与巨噬细胞引物相关的 T 细胞衍生细胞因子。在这篇综述中,我将概述最近开发的利用细胞因子信号增强 CAR-T 细胞功能的合成生物学方法。我还将讨论预防或减轻 CAR-T 细胞相关毒性的治疗靶分子。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
期刊最新文献
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