Inserm, U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Immunity and Cancer, Institut Paoli Calmettes, Aix Marseille Université, Marseille, France.
Immunomonitoring Platform, Institut Paoli Calmettes, Marseille, France.
Adv Exp Med Biol. 2020;1273:91-104. doi: 10.1007/978-3-030-49270-0_5.
Gamma delta (γδ) T cells which combine both innate and adaptive potential have extraordinary properties. Indeed, their strong cytotoxic and pro-inflammatory activity allows them to kill a broad range of tumor cells. Several studies have demonstrated that γδ T cells are an important component of tumor-infiltrated lymphocytes in patients affected by different types of cancer. Tumor-infiltrating γδ T cells are also considered as a good prognostic marker in many studies, though the presence of these cells is associated with poor prognosis in breast and colon cancers. The tumor microenvironment seems to drive γδ T-cell differentiation toward a tumor-promoting or a tumor-controlling phenotype, which suggests that some tumor microenvironments can limit the effectiveness of γδ T cells.The major γδ T-cell subsets in human are the Vγ9Vδ2 T cells that are specifically activated by phosphoantigens. This unique antigenic activation process operates in a framework that requires the expression of butyrophilin 3A (BTN3A) molecules. Interestingly, there is some evidence that BTN3A expression may be regulated by the tumor microenvironment. Given their strong antitumoral potential, Vγ9Vδ2 T cells are used in therapeutic approaches either by ex vivo culture and amplification, and then adoptive transfer to patients or by direct stimulation to propagate in vivo. These strategies have demonstrated promising initial results, but greater potency is needed. Combining Vγ9Vδ2 T-cell immunotherapy with systemic approaches to restore antitumor immune response in tumor microenvironment may improve efficacy.In this chapter, we first review the basic features of γδ T cells and their roles in the tumor microenvironment and then analyze the advances about the understanding of these cells' activation in tumors and why this represent unique challenges for therapeutics, and finally we discuss γδ T-cell-based therapeutic strategies and future perspectives of their development.
γδ（γδ）T 细胞兼具先天和适应性潜能，具有非凡的特性。事实上，它们强大的细胞毒性和促炎活性使它们能够杀死广泛的肿瘤细胞。多项研究表明，γδ T 细胞是受不同类型癌症影响的患者肿瘤浸润淋巴细胞的重要组成部分。在许多研究中，肿瘤浸润的 γδ T 细胞也被认为是一个良好的预后标志物，尽管这些细胞的存在与乳腺癌和结肠癌的预后不良有关。肿瘤微环境似乎促使 γδ T 细胞向促进肿瘤或控制肿瘤的表型分化，这表明某些肿瘤微环境可以限制 γδ T 细胞的有效性。人类中主要的 γδ T 细胞亚群是 Vγ9Vδ2 T 细胞，这些细胞被磷酸抗原特异性激活。这种独特的抗原激活过程在需要表达丁酰膦蛋白 3A（BTN3A）分子的框架内运行。有趣的是，有一些证据表明 BTN3A 的表达可能受到肿瘤微环境的调节。鉴于其强大的抗肿瘤潜力，Vγ9Vδ2 T 细胞被用于治疗方法，无论是通过体外培养和扩增，然后过继转移给患者，还是通过直接刺激在体内增殖。这些策略已经证明了有希望的初步结果，但需要更大的效力。将 Vγ9Vδ2 T 细胞免疫疗法与系统方法相结合，以恢复肿瘤微环境中的抗肿瘤免疫反应，可能会提高疗效。在本章中，我们首先回顾了 γδ T 细胞的基本特征及其在肿瘤微环境中的作用，然后分析了对这些细胞在肿瘤中激活的理解的进展，以及为什么这对治疗学构成独特的挑战，最后我们讨论了基于 γδ T 细胞的治疗策略及其未来发展前景。
