Calcium Nanoparticles to Stimulate Dendritic Cell and Boost T cell Immunity Against Cancer

Dendritic cells (DCs) are the most effective type of antigen-representing cells (APCs).^[1] DCs capture tumor antigens, process them, and migrate to the T cell zone in tumor-draining lymph nodes (TDLNs) where they prime T cells through cross-presentation. During this process, DCs manifest upregulated antigen-presenting molecules (major histocompatibility complexes MHC-I and MHC-II) and costimulatory molecules (CD80, CD86 and CD40),^[2] and elevated secretion of cytokines such as interleukin 12 (IL-12) and tumor necrosis factor-α (TNF-α). After cross-presentation, cytotoxic T cells (CTLs) travel back to tumors where they kill cancer cells in an antigen-specific manner. However, tumor microenvironment (TME) is rich in immunosuppressive factors, which may suppress DC maturation and migration thus curbing T cell immunity. Many have explored immune modulators that can stimulate DCs to boost immune responses. Despite the progress, however, selectively and safely activating DCs in vivo remain elusive. DC responses are largely governed by Ca²⁺ signaling. During maturation, intracellular calcium of DCs is elevated, triggering signaling cascades that result in upregulation of costimulatory and antigen-presenting molecules.^[3] Herein, we investigate calcium nanoparticles as a novel type of immune modulator for DCs. We postulate that calcium nanoparticles can be taken up by DCs can slowly release calcium therein, in turn promoting DC maturation, migration, and cross-presentation. We tested the hypothesis first in vitro with bone marrow derived dendritic cells (BMDCs) and then in vivo in B16-OVA tumor models.

References

[1]. Kapsenberg, M.L. Nature Reviews Immunology 2003, 3(12), 984-993

[2]. Zitvogel, L. & Kroemer, G. Nature Reviews Immunology 2006, 6(10), 715-727

[3]. Frances R.B. et al., Journal of Cell Science 2012, 125, 5591-5596