Department of Chemistry, University of Georgia, Athens, GA, USA.
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Nat Commun. 2024 Nov 21;15(1):10095. doi: 10.1038/s41467-024-54402-y.
Calcium signaling plays a crucial role in the activation of T lymphocytes. However, modulating calcium levels to control T cell activation in vivo remains a challenge. In this study, we investigate T cell activation using 12-myristate 13-acetate (PMA)-encapsulated CaCO nanoparticles. We find that anti-PD-1 antibody-conjugated CaCO nanoparticles can be internalized by T cells via receptor-mediated endocytosis and then gradually release calcium. This results in an increase in cytosolic calcium, which triggers the activation of NFAT and NF-κB pathways, especially when the surface of the CaCO nanoparticles is loaded with PMA. Animal studies demonstrate that the PMA-loaded calcium nanoparticles enhance the activation and proliferation of cytotoxic T cells, leading to improved tumor suppression without additional toxicity. When tested in metastatic tumor models, T cells loaded with the calcium nanoparticles prior to adoptive cell transfer control tumor growth better, resulting in prolonged animal survival. Our approach offers an alternative T cell activation strategy to potentiate immunotherapy by targeting a fundamental signaling pathway.
钙信号在 T 淋巴细胞的激活中起着至关重要的作用。然而，在体内调节钙水平以控制 T 细胞的激活仍然是一个挑战。在这项研究中，我们使用包被有 12-肉豆蔻酸 13-乙酸酯（PMA）的 CaCO3 纳米颗粒来研究 T 细胞的激活。我们发现，抗 PD-1 抗体偶联的 CaCO3 纳米颗粒可以通过受体介导的内吞作用被 T 细胞内化，然后逐渐释放钙离子。这导致细胞溶质钙的增加，从而触发 NFAT 和 NF-κB 途径的激活，特别是当 CaCO3 纳米颗粒的表面负载有 PMA 时。动物研究表明，负载 PMA 的钙纳米颗粒增强了细胞毒性 T 细胞的激活和增殖，从而在没有额外毒性的情况下提高了肿瘤抑制作用。在转移性肿瘤模型中进行测试时，在过继细胞转移前负载钙纳米颗粒的 T 细胞更好地控制肿瘤生长，从而延长了动物的存活时间。我们的方法提供了一种替代的 T 细胞激活策略，通过靶向一个基本的信号通路来增强免疫疗法。
