Dendritic Cell-Targeted\nNanoparticles Enhance T Cell\nActivation and Antitumor Immune Responses by Boosting Antigen Presentation\nand Blocking PD-L1 Pathways

Dendritic cells (DCs) within the tumor microenvironment\n(TME) have\nan insufficient capacity to activate T cells through antigen presentation.\nFurthermore, the programmed cell-death ligand 1 (PD-L1), abundantly\nexpressed on tumor-associated DCs, binds the programmed cell-death\n1 (PD-1)-positive T cells and suppresses their immune function. The\nbinding of PD-L1 to CD80 (B7.1) on the same DC via <i>cis</i>-interactions further prevents T cell costimulation through CD28.\nHere, we present a strategy to simultaneously promote antigen cross-presentation\nand block the inhibitory interactions of PD-L1 on DCs to amplify T\ncell-mediated antitumor responses within the TME. Mesoporous silica\nnanoparticles (MSNPs) were loaded with clotrimazole (CLT) to boost\nMHC II-mediated antigen presentation by DCs, surface-modified with\nmannose to target CD206 on DCs, and then decorated with PD-L1 binding\npeptide (PDL1bp) to block PD-L1-mediated interactions. PDL1bp was\ncleaved from the mannosylated and CLT-loaded MSNPs (MSNP-MaN/CLT)\nunder conditions simulating the TME and tethered to PD-L1 to reverse\nCD80 sequestration on DC2.4 cells. The blocking of PD-L1 by PDL1bp-decorated\nNPs (MSNP-MaN-PDL1bp) increased the cellular interactions between\nDC2.4 and EL4 T cells and the amount of IL-2 secretion. The MSNP-MaN/CLT\nwere taken up rapidly by DC2.4 cells, promoted MHC II presentation\nof hen egg lysozyme (HEL), and increased IL-2 production from HEL\nantigen-primed 3A9 T cells, which was further enhanced by PDL1bp.\nIn vivo investigation revealed that administration of the CLT-loaded\nand PDL1bp-functionalized MSNPs remarkably inhibited subcutaneous\nB16-F10 melanoma tumor growth when compared with anti-PD-L1 therapy.\nMSNP-MaN-PDL1bp/CLT treatment upregulated the levels of effector molecules\nsuch as granzyme B and proinflammatory cytokines (IFNγ and INFα)\nin the tumor tissue, indicating antitumoral T cell responses. This\nstrategy of utilizing nanoparticles to trigger DC activation while\npromoting T cell stimulation can be used to amplify the antitumor\nT cell responses and represents a promising alternative to anti-PD-L1\nimmunotherapy.