Journal
ACS NANO
Volume 11, Issue 10, Pages 10135-10146Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.7b04717
Keywords
siRNA delivery; polyelectrolyte carrier; immune checkpoint blockade; mTOR pathway; PD-L1; B16F10 melanoma
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Funding
- NSF [DMR-1056997]
- NIH [R01 CA199663, R01 EB017791]
- Intramural Research Program (Global RNAi Carrier Initiative) of KIST
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Programmed cell death protein-1 (PD-1) is a prominent immune checkpoint receptor interacting with its ligand, programmed cell death protein ligand-1 (PD-L1, B7-Hi). The PD-1/PD-L1 interaction induces functional exhaustion of tumor-reactive cytotoxic T cells and, thus, interferes with antitumor T-cell immunity. In addition, PD-1/PD-L1 interaction promotes tumorigenesis via the mTOR. signaling pathway in a group of cancers including melanoma. Based on the dual functions of PD-1/PD-L1 interactions in tumor progression, we hypothesize that siRNA targeting PD-L1 (siPD-L1) will suppress melanoma growth, acting on both immune checkpoint and intrinsic tumorigenesis pathways. We tested this hypothesis by delivering siPD-L1 with a polymeric carrier (pd) consisting of disulfide-cross-linked polyethylenimine (CLPEI) and dermatan sulfate (DS), which we previously found to have a specific interaction with CD146-positive B16F10 melanoma cells. The siPD-L1/pd suppressed the expression of PD-Ll in the interferon-gamma (IFN-gamma)-challenged B16F10 melanoma cells in a cell type dependent manner and attenuated the expression of tumor-specific genes in B16F10 cells. siPD-Ll/pd suppressed the B16F10 melanoma growth in C57BL/6 immune-competent mice with increased tumor-specific immunity. siPD-Ll/pd also suppressed melanoma growth in immune-compromised nude mice. Both animals showed a positive correlation between PD-L1 and p-S6k (a marker of mTOR pathway activation) expression in tumors. These results indicate that the siPD-L1/pd complex attenuates melanoma growth in both T-cell-dependent and independent mechanisms.
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