T 细胞的机械免疫工程用于治疗应用。

Mechanical Immunoengineering of T cells for Therapeutic Applications.

出版信息

Acc Chem Res. 2020 Dec 15;53(12):2777-2790. doi: 10.1021/acs.accounts.0c00486. Epub 2020 Dec 1.

Abstract

T cells, a key component in adaptive immunity, are central to many immunotherapeutic modalities aimed at treating various diseases including cancer, infectious diseases, and autoimmune disorders. The past decade has witnessed tremendous progress in immunotherapy, which aims at activation or suppression of the immune responses for disease treatments. Most strikingly, cancer immunotherapy has led to curative responses in a fraction of patients with relapsed or refractory cancers. However, extending those clinical benefits to a majority of cancer patients remains challenging. In order to improve both efficacy and safety of T cell-based immunotherapies, significant effort has been devoted to modulating biochemical signals to enhance T cell proliferation, effector functions, and longevity. Such strategies include discovery of new immune checkpoints, design of armored chimeric antigen receptor (CAR) T cells, and targeted delivery of stimulatory cytokines and so on.Despite the intense global research effort in developing novel cancer immunotherapies, a major dimension of the interactions between cancer and the immune system, its biomechanical aspect, has been largely underappreciated. Throughout their lifecycle, T cells constantly survey a multitude of organs and tissues and experience diverse biomechanical environments, such as shear force in the blood flow and a broad range of tissue stiffness. Furthermore, biomechanical properties of tissues or cells may be altered in disease and inflammation. Biomechanical cues, including both passive mechanical cues and active mechanical forces, have been shown to govern T cell development, activation, migration, differentiation, and effector functions. In other words, T cells can sense, respond to, and adapt to both passive mechanical cues and active mechanical forces.Biomechanical cues have been intensively studied at a fundamental level but are yet to be extensively incorporated in the design of immunotherapies. Nonetheless, the growing knowledge of T cell mechanobiology has formed the basis for the development of novel engineering strategies to mechanically modulate T cell immunity, a nascent field that we termed "mechanical immunoengineering". Mechanical immunoengineering exploits biomechanical cues (e.g., stiffness and external forces) to modulate T cell differentiation, proliferation, effector functions, etc., for diagnostic or therapeutic applications. It provides an additional dimension, complementary to traditional modulation of biochemical cues (e.g., antigen density and co-stimulatory signals), to tailor T cell immune responses and enhance therapeutic outcomes. For example, stiff antigen-presenting matrices have been shown to enhance T cell proliferation independently of the intensity of biochemical stimulatory signals. Current strategies of mechanical immunoengineering of T cells can be categorized into two major fields including passive mechanical cue-oriented and active force-oriented strategies. In this Account, we first present a brief overview of T cell mechanobiology. Next, we summarize recent advances in mechanical immunoengineering, discuss the roles of chemistry and material science in the development of these engineering strategies, and highlight potential therapeutic applications. Finally, we present our perspective on the future directions in mechanical immunoengineering and critical steps to translate mechanical immunoengineering strategies into therapeutic applications in the clinic.

摘要

T 细胞是适应性免疫的关键组成部分,是许多旨在治疗各种疾病(包括癌症、传染病和自身免疫性疾病)的免疫治疗模式的核心。过去十年中,免疫疗法取得了巨大进展,旨在激活或抑制免疫反应以进行疾病治疗。最引人注目的是,癌症免疫疗法已导致部分复发或难治性癌症患者产生治愈反应。然而,将这些临床益处扩展到大多数癌症患者仍然具有挑战性。为了提高基于 T 细胞的免疫疗法的疗效和安全性,人们付出了巨大的努力来调节生化信号,以增强 T 细胞的增殖、效应功能和寿命。这些策略包括发现新的免疫检查点、设计装甲嵌合抗原受体(CAR)T 细胞以及靶向递送刺激细胞因子等。

尽管全球在开发新型癌症免疫疗法方面进行了大量研究,但癌症与免疫系统相互作用的一个重要方面,即其生物力学方面,在很大程度上仍未得到重视。在其生命周期中,T 细胞不断监测多种器官和组织,并经历多种生物力学环境,例如血流中的剪切力和广泛的组织硬度。此外,组织或细胞的生物力学特性可能在疾病和炎症中发生改变。生物力学线索,包括被动机械线索和主动机械力,已被证明可控制 T 细胞的发育、激活、迁移、分化和效应功能。换句话说,T 细胞可以感知、响应和适应被动机械线索和主动机械力。

生物力学线索在基础水平上得到了深入研究,但尚未广泛应用于免疫疗法的设计中。尽管如此,T 细胞力学生物学的不断发展知识为开发新型工程策略以机械调节 T 细胞免疫提供了基础,这是一个新兴领域,我们称之为“机械免疫工程”。机械免疫工程利用生物力学线索(例如,刚度和外力)来调节 T 细胞分化、增殖、效应功能等,用于诊断或治疗应用。它提供了一个额外的维度,补充了传统的生化线索调节(例如,抗原密度和共刺激信号),以定制 T 细胞免疫反应并增强治疗效果。例如,已证明刚性抗原呈递基质可独立于生化刺激信号的强度增强 T 细胞增殖。目前的 T 细胞机械免疫工程策略可分为两个主要领域,包括被动机械线索导向和主动力导向策略。在本报告中,我们首先简要介绍 T 细胞力学生物学。接下来,我们总结机械免疫工程的最新进展,讨论化学和材料科学在这些工程策略发展中的作用,并强调潜在的治疗应用。最后,我们提出了对机械免疫工程未来方向的看法,并介绍了将机械免疫工程策略转化为临床治疗应用的关键步骤。

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