Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Allston, Massachusetts 02134, United States.
Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, United States.
ACS Nano. 2023 Aug 22;17(16):15918-15930. doi: 10.1021/acsnano.3c03980. Epub 2023 Aug 11.
Natural killer (NK) cell therapies have emerged as a potential therapeutic approach to various cancers. Their efficacy, however, is limited by their low persistence and anergy. Current approaches to sustain NK cell persistence include genetic modification, activation via pretreatment, or coadministration of supporting cytokines or antibodies. Such supporting therapies exhibit limited efficacy , in part due to the reversal of their effect within the immunosuppressive tumor microenvironment and off-target toxicity. Here, we report a material-based approach to address this challenge. Specifically, we describe the use of polymeric micropatches as a platform for sustained, targeted activation of NK cells, an approach referred to as microparticles as cell engagers (MACE). Poly(lactide--glycolic) acid (PLGA) micropatches, 4-8 μm in diameter and surface-modified with NK cell receptor targeting antibodies, exhibited strong adhesion to NK cells and induced their activation without the need of coadministered cytokines. The activation induced by MACE was greater than that induced by nanoparticles, attesting to the crucial role of MACE geometry in the activation of NK cells. MACE-bound NK cells remained viable and exhibited trans-endothelial migration and antitumor activity . MACE-bound NK cells activated T cells, macrophages, and dendritic cells . Adoptive transfer of NK-MACE also demonstrated superior antitumor efficacy in a mouse melanoma lung metastasis model compared to unmodified NK cells. Overall, MACE offers a simple, scalable, and effective way of activating NK cells and represents an attractive platform to improve the efficacy of NK cell therapy.
自然杀伤 (NK) 细胞疗法已成为治疗各种癌症的一种有潜力的治疗方法。然而，其疗效受到其低持久性和无能的限制。目前维持 NK 细胞持久性的方法包括遗传修饰、预处理激活或共施用支持细胞因子或抗体。这些支持性治疗方法的疗效有限，部分原因是其在免疫抑制肿瘤微环境中的作用逆转和脱靶毒性。在这里，我们报告了一种基于材料的方法来解决这一挑战。具体来说，我们描述了使用聚合物微贴片作为持续、靶向激活 NK 细胞的平台，这种方法称为作为细胞衔接器的微粒（MACE）。直径为 4-8 μm 的聚（乳酸-共-乙醇酸）（PLGA）微贴片，表面修饰有 NK 细胞受体靶向抗体，与 NK 细胞表现出强烈的黏附，并在不需要共施用细胞因子的情况下诱导其激活。MACE 诱导的激活大于纳米颗粒诱导的激活，证明了 MACE 几何形状在激活 NK 细胞中的关键作用。MACE 结合的 NK 细胞保持存活，并表现出跨内皮迁移和抗肿瘤活性。MACE 结合的 NK 细胞激活了 T 细胞、巨噬细胞和树突状细胞。与未修饰的 NK 细胞相比，NK-MACE 的过继转移在小鼠黑色素瘤肺转移模型中也表现出更好的抗肿瘤疗效。总体而言，MACE 提供了一种简单、可扩展且有效的激活 NK 细胞的方法，代表了改善 NK 细胞治疗效果的有吸引力的平台。
