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Dendritic Cell-Targeted Nanoparticles Enhance T Cell Activation and Antitumor Immune Responses by Boosting Antigen Presentation and Blocking PD-L1 Pathways.
- Source :
-
ACS applied materials & interfaces [ACS Appl Mater Interfaces] 2024 Oct 09; Vol. 16 (40), pp. 53577-53590. Date of Electronic Publication: 2024 Sep 30. - Publication Year :
- 2024
-
Abstract
- Dendritic cells (DCs) within the tumor microenvironment (TME) have an insufficient capacity to activate T cells through antigen presentation. Furthermore, the programmed cell-death ligand 1 (PD-L1), abundantly expressed on tumor-associated DCs, binds the programmed cell-death 1 (PD-1)-positive T cells and suppresses their immune function. The binding of PD-L1 to CD80 (B7.1) on the same DC via cis -interactions further prevents T cell costimulation through CD28. Here, we present a strategy to simultaneously promote antigen cross-presentation and block the inhibitory interactions of PD-L1 on DCs to amplify T cell-mediated antitumor responses within the TME. Mesoporous silica nanoparticles (MSNPs) were loaded with clotrimazole (CLT) to boost MHC II-mediated antigen presentation by DCs, surface-modified with mannose to target CD206 on DCs, and then decorated with PD-L1 binding peptide (PDL1bp) to block PD-L1-mediated interactions. PDL1bp was cleaved from the mannosylated and CLT-loaded MSNPs (MSNP-MaN/CLT) under conditions simulating the TME and tethered to PD-L1 to reverse CD80 sequestration on DC2.4 cells. The blocking of PD-L1 by PDL1bp-decorated NPs (MSNP-MaN-PDL1bp) increased the cellular interactions between DC2.4 and EL4 T cells and the amount of IL-2 secretion. The MSNP-MaN/CLT were taken up rapidly by DC2.4 cells, promoted MHC II presentation of hen egg lysozyme (HEL), and increased IL-2 production from HEL antigen-primed 3A9 T cells, which was further enhanced by PDL1bp. In vivo investigation revealed that administration of the CLT-loaded and PDL1bp-functionalized MSNPs remarkably inhibited subcutaneous B16-F10 melanoma tumor growth when compared with anti-PD-L1 therapy. MSNP-MaN-PDL1bp/CLT treatment upregulated the levels of effector molecules such as granzyme B and proinflammatory cytokines (IFNγ and INFα) in the tumor tissue, indicating antitumoral T cell responses. This strategy of utilizing nanoparticles to trigger DC activation while promoting T cell stimulation can be used to amplify the antitumor T cell responses and represents a promising alternative to anti-PD-L1 immunotherapy.
- Subjects :
- Animals
Mice
Mice, Inbred C57BL
Female
Cell Line, Tumor
Silicon Dioxide chemistry
Humans
Dendritic Cells immunology
Dendritic Cells drug effects
Dendritic Cells metabolism
B7-H1 Antigen metabolism
Nanoparticles chemistry
Antigen Presentation drug effects
T-Lymphocytes immunology
T-Lymphocytes drug effects
Lymphocyte Activation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1944-8252
- Volume :
- 16
- Issue :
- 40
- Database :
- MEDLINE
- Journal :
- ACS applied materials & interfaces
- Publication Type :
- Academic Journal
- Accession number :
- 39344665
- Full Text :
- https://doi.org/10.1021/acsami.4c12821