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

Gijung Kwak, Dongkyu Kim, Gi Hoon Nam, Sun Young Wang, In-San Kim, Sun Hwa Kim, Ick Chan Kwon, Yoon Yeo

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)10135-10146
Number of pages12
JournalACS Nano
Volume11
Issue number10
DOIs
Publication statusPublished - 2017 Oct 24

Keywords

  • B16F10 melanoma
  • immune checkpoint blockade
  • mTOR pathway
  • PD-L1
  • polyelectrolyte carrier
  • siRNA delivery

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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