Calcium Nanoparticles to Enhance Immuno-Radiotherapy

About This Grant

Abstract Immune checkpoint blockade has become a cornerstone treatment for many solid tumors. However, not all patients respond effectively to this therapy. To enhance its efficacy, researchers are exploring the combination of radiation and immunotherapy, a strategy known as radio-immunotherapy. Despite its promise, radio- immunotherapy has not consistently demonstrated clinical benefit, in part due to a lack of activated dendritic cells (DCs) within tumors. Among these immune cells, a specific subset known as cDC1s plays a crucial role in antigen cross-presentation to T cells in the tumor-draining lymph nodes (TDLNs) to initiate anti-tumor immune responses. Emerging studies suggest that cDC1s in the TDLNs are also critical targets for immune checkpoint inhibitors. Tumors resistant to immunotherapy or radio-immunotherapy often exhibit low cDC1 levels, and their migration to TDLNs can be impeded by the immunosuppressive tumor microenvironment. This project aims to develop a calcium nanoparticle-based combinatory treatment to enhance radio- immunotherapy by improving both tumor infiltration and TDLN migration of cDC1s. We hypothesize that surface- engineered calcium nanoparticles, termed αCaNPs, can selectively deliver calcium, a key second messenger for immune cell migration, into circulating cDC1s, thereby enhancing their tumor infiltration in response to chemotactic signals. In addition, we anticipate that αCaNPs, by elevating cytosolic calcium levels, will promote cDC1 maturation inside tumors and afferent migration to TDLNs. Under immune checkpoint blockade with PD- L1 antibody, we expect that cDC1s will prime T cells in the TDLNs, leading to clonal expansion and robust anti- tumor immunity. To evaluate the efficacy of this approach, we will use murine models of head and neck squamous cell carcinoma (HNSCC). If successful, our technology could be extended to other cancers currently under intensive clinical investigation for radio-immunotherapy.