Programmed Cell Death Protein Ligand‑1 Silencing with Polyethylenimine–Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth

• Published in: ACS nano Vol. 11; no. 10; pp. 10135 - 10146
• Main Authors: Kwak, Gijung, Kim, Dongkyu, Nam, Gi-hoon, Wang, Sun Young, Kim, In-San, Kim, Sun Hwa, Kwon, Ick-Chan, Yeo, Yoon
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.10.2017
• Subjects: siRNA delivery; mTOR pathway; PD-L1; polyelectrolyte carrier; B16F10 melanoma; immune checkpoint blockade
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.7b04717

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-H1). 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-L1 in the interferon-γ (IFN-γ)-challenged B16F10 melanoma cells in a cell-type dependent manner and attenuated the expression of tumor-specific genes in B16F10 cells. siPD-L1/pd suppressed the B16F10 melanoma growth in C57BL/6 immune-competent mice with increased tumor-specific immunity. siPD-L1/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.