Weiss Lea, Schluck Marjolein, Classens René, de Jonge Paul K J D, van der Waart Anniek, Nguyen Khue G, Nguyen Tam T, Zaharoff David A, Malmberg Karl-Johan, Dolstra Harry, Figdor Carl G, Sohlberg Ebba, Hammink Roel
Department of Medical BioSciences, Radboudumc, Geert Grooteplein 26, Nijmegen, GA 6525, the Netherlands; Institute for Chemical Immunology, Nijmegen, GA 6525, the Netherlands; Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, GA 6525, Netherlands.
Department of Medical BioSciences, Radboudumc, Geert Grooteplein 26, Nijmegen, GA 6525, the Netherlands; Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, GA 6525, Netherlands.
Acta Biomater. 2025 Jan 1;191:386-397. doi: 10.1016/j.actbio.2024.11.012. Epub 2024 Nov 9.
Immunotherapies are a powerful strategy to treat cancer by modulating the immune system to raise an anti-tumor immune response. A prime example of immunotherapies are cytokines - small immunomodulatory molecules that are widely used to stimulate immune cells. Undirected administration of cytokines, however, can cause severe side effects, preventing the use of potent cytokines, such as Interleukin (IL)-12, which induces IFNγ responses by cytotoxic effector lymphocytes, including NK cells. Biomaterials, like nanoparticles, can encapsulate IL-12 and accumulate at the tumor site to alleviate side effects. Yet, the released IL-12 might not be directly targeted to extracellular IL-12 receptors on the specific effector cells, thereby potentially compromising the cytokine's therapeutic efficacy. Here, we develop a polymer-based platform to target NK cells, which we call immunofilaments. Immunofilaments are nanosized linear polymers that present an anti-CD16 antibody and IL-12 effectively to NK cells and lead to synergistic NK cell activation as highlighted by an increase in TNFα and IFNγ production and upregulation of multiple activation markers, including CD25, CD69, and degranulation marker CD107a. NK cell proliferation is enhanced in the presence of both anti-CD16 antibody and IL-12 compared to giving IL-12 separately. Finally, we demonstrate that the IF platform is suitable for in vivo applications, as immunofilaments readily activate human NK cells upon administration to mice. STATEMENT OF SIGNIFICANCE: IL-12 is a potent cytokine that stimulates IFNγ responses in NK cells, which supports an anti-tumor immune response. Due to its high potency, the delivery of IL-12 needs to be highly controlled to prevent severe adverse side effects, which can be achieved by using biomaterials. This study shows that nanosized polymers termed Immunofilaments can be used to immobilize IL-12 and effectively target and activate NK cells by co-conjugation of anti-CD16 antibodies. This work is a prime example of careful engineering of innovative biomaterials to improve immunotherapy.
免疫疗法是一种通过调节免疫系统以引发抗肿瘤免疫反应来治疗癌症的强大策略。免疫疗法的一个典型例子是细胞因子——广泛用于刺激免疫细胞的小型免疫调节分子。然而，无定向施用细胞因子会导致严重的副作用，从而阻碍了诸如白细胞介素（IL）-12等强效细胞因子的使用，IL-12可诱导包括自然杀伤细胞（NK细胞）在内的细胞毒性效应淋巴细胞产生IFNγ反应。诸如纳米颗粒之类的生物材料可以包裹IL-12并在肿瘤部位积聚以减轻副作用。然而，释放的IL-12可能不会直接靶向特定效应细胞上的细胞外IL-12受体，从而可能会损害细胞因子的治疗效果。在此，我们开发了一种基于聚合物的平台来靶向NK细胞，我们将其称为免疫丝。免疫丝是纳米级的线性聚合物，可有效地将抗CD16抗体和IL-12呈递给NK细胞，并导致NK细胞协同激活，这表现为TNFα和IFNγ产生增加以及包括CD25、CD69和脱颗粒标记物CD107a在内的多种激活标记物上调。与单独给予IL-12相比，在同时存在抗CD16抗体和IL-12的情况下，NK细胞增殖增强。最后，我们证明了免疫丝平台适用于体内应用，因为免疫丝在施用于小鼠后很容易激活人NK细胞。重要性声明：IL-12是一种强效细胞因子，可刺激NK细胞产生IFNγ反应，从而支持抗肿瘤免疫反应。由于其高效性，IL-12的递送需要高度控制以防止严重的不良副作用，这可以通过使用生物材料来实现。这项研究表明，被称为免疫丝的纳米级聚合物可用于固定IL-12，并通过抗CD16抗体的共缀合有效地靶向和激活NK细胞。这项工作是精心设计创新生物材料以改善免疫疗法的一个典型例子。
