Michielon E, King L A, Waaijman T, Veth M, Spiekstra S W, van der Vliet H J, Gibbs S, de Gruijl T D
Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center Location Vrije Universiteit Amsterdam, Amsterdam.
Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam.
Immunooncol Technol. 2024 Jul 10;24:100724. doi: 10.1016/j.iotech.2024.100724. eCollection 2024 Dec.
Despite considerable advancements in cancer immunotherapy, advanced melanoma still presents a substantial clinical challenge. In an effort to explore treatment options, we examined the immunotherapeutic potential of effector Vγ9Vδ2-T cells in a three-dimensional (3D) human organotypic melanoma-in-skin (Mel-RhS) model.
Vγ9Vδ2-T cells were introduced into Mel-RhS via intradermal injection and cultured within the tissue microenvironment for up to 3 days.
Vγ9Vδ2-T cells remained viable for up to 3 days and were in close proximity to or within tumor nests. Upon Mel-RhS dissociation, a fraction was shown to be decorated by melanoma-associated chondroitin sulfate proteoglycan (MCSP), demonstrating their ability to actively navigate the tumor microenvironment and trogocytose cancer cells. Investigation into the apparent trogocytosis revealed an enhanced activated state of MCSP-decorated Vγ9Vδ2-T cells, evidenced by increased expression levels of 4-1BB, NKp44, programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1), compared with their MCSP counterpart. These findings suggest that Vγ9Vδ2-T cells, upon successfully contacting melanoma cells, actively recognize and acquire MCSP from these malignant cells. Evidence of actual tumor cell elimination, although not significant, was only obtained after preincubation of Mel-RhS with pamidronate, a phosphoantigen-inducing agent, indicating the need for additional T cell receptor-mediated signaling for Vγ9Vδ2-T cells to reach their full oncolytic potential.
This study highlights the viability and persistence of Vγ9Vδ2-T cells within the 3D microenvironment, their migratory and antitumor functionality, and the suitability of the model for testing T cell-based therapies, contributing both to the understanding of Vγ9Vδ2-T cell biology and their application in cancer immunotherapy.
尽管癌症免疫疗法取得了显著进展，但晚期黑色素瘤仍然是一个重大的临床挑战。为了探索治疗方案，我们在三维（3D）人皮肤型黑色素瘤（Mel-RhS）模型中研究了效应性Vγ9Vδ2-T细胞的免疫治疗潜力。
通过皮内注射将Vγ9Vδ2-T细胞引入Mel-RhS，并在组织微环境中培养长达3天。
Vγ9Vδ2-T细胞在长达3天内保持存活，并与肿瘤巢紧密相邻或位于肿瘤巢内。在Mel-RhS解离后，一部分细胞被证明带有黑色素瘤相关硫酸软骨素蛋白聚糖（MCSP），表明它们有能力在肿瘤微环境中主动游走并进行肿瘤细胞的穿胞作用。对明显的穿胞作用的研究表明，与未携带MCSP的Vγ9Vδ2-T细胞相比，携带MCSP的Vγ9Vδ2-T细胞激活状态增强，这通过4-1BB、NKp44、程序性细胞死亡蛋白-1（PD-1）和程序性死亡配体-1（PD-L1）表达水平的增加得以证明。这些发现表明，Vγ9Vδ2-T细胞在成功接触黑色素瘤细胞后，会主动识别并从这些恶性细胞中获取MCSP。虽然实际肿瘤细胞清除的证据不显著，但仅在Mel-RhS与帕米膦酸（一种磷酸抗原诱导剂）预孵育后才获得，这表明Vγ9Vδ2-T细胞需要额外的T细胞受体介导的信号传导才能发挥其完全的溶瘤潜力。
本研究突出了Vγ9Vδ2-T细胞在3D微环境中的活力和持久性、它们的迁移和抗肿瘤功能，以及该模型对基于T细胞疗法的测试的适用性，这有助于理解Vγ9Vδ2-T细胞生物学及其在癌症免疫治疗中的应用。
