Calcium nanoparticles target and activate T cells to enhance anti-tumor function
Wei Yang, Zhizi Feng, Xinning Lai, Jianwen Li, Zhengwei Cao, Fangchao Jiang, Fanghui Chen, Shuyue Zhan, Feng Kong, Li Yang, Yong Teng, Wendy T. Watford, Gang Zhou, Jin Xie
Abstract
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 CaCO3 nanoparticles. We find that anti-PD-1 antibody-conjugated CaCO3 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 CaCO3 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. Calcium signalling is an essential feature of T cell activation. Here authors employ CaCO3 nanoparticles to facilitate the expansion and cytotoxic function of therapeutic T cells via enhanced intracellular release of calcium.