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

19 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

Fingerprint

Polyethyleneimine
Dermatan Sulfate
Apoptosis Regulatory Proteins
apoptosis
Cell death
Small Interfering RNA
Tumors
sulfates
tumors
Ligands
T-cells
proteins
Proteins
ligands
immunity
cells
mice
interactions
interferon
Programmed Cell Death 1 Receptor

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)

Cite this

Programmed Cell Death Protein Ligand-1 Silencing with Polyethylenimine-Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth. / Kwak, Gijung; Kim, Dongkyu; Nam, Gi Hoon; Wang, Sun Young; Kim, In-San; Kim, Sun Hwa; Kwon, Ick Chan; Yeo, Yoon.

In: ACS Nano, Vol. 11, No. 10, 24.10.2017, p. 10135-10146.

Research output: Contribution to journalArticle

Kwak, Gijung ; Kim, Dongkyu ; Nam, Gi Hoon ; Wang, Sun Young ; Kim, In-San ; Kim, Sun Hwa ; Kwon, Ick Chan ; Yeo, Yoon. / Programmed Cell Death Protein Ligand-1 Silencing with Polyethylenimine-Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth. In: ACS Nano. 2017 ; Vol. 11, No. 10. pp. 10135-10146.
@article{6e7289aabdf4420e9faecb759c72cfbe,
title = "Programmed Cell Death Protein Ligand-1 Silencing with Polyethylenimine-Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth",
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.",
keywords = "B16F10 melanoma, immune checkpoint blockade, mTOR pathway, PD-L1, polyelectrolyte carrier, siRNA delivery",
author = "Gijung Kwak and Dongkyu Kim and Nam, {Gi Hoon} and Wang, {Sun Young} and In-San Kim and Kim, {Sun Hwa} and Kwon, {Ick Chan} and Yoon Yeo",
year = "2017",
month = "10",
day = "24",
doi = "10.1021/acsnano.7b04717",
language = "English",
volume = "11",
pages = "10135--10146",
journal = "ACS Nano",
issn = "1936-0851",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Programmed Cell Death Protein Ligand-1 Silencing with Polyethylenimine-Dermatan Sulfate Complex for Dual Inhibition of Melanoma Growth

AU - Kwak, Gijung

AU - Kim, Dongkyu

AU - Nam, Gi Hoon

AU - Wang, Sun Young

AU - Kim, In-San

AU - Kim, Sun Hwa

AU - Kwon, Ick Chan

AU - Yeo, Yoon

PY - 2017/10/24

Y1 - 2017/10/24

N2 - 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.

AB - 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.

KW - B16F10 melanoma

KW - immune checkpoint blockade

KW - mTOR pathway

KW - PD-L1

KW - polyelectrolyte carrier

KW - siRNA delivery

UR - http://www.scopus.com/inward/record.url?scp=85033370647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033370647&partnerID=8YFLogxK

U2 - 10.1021/acsnano.7b04717

DO - 10.1021/acsnano.7b04717

M3 - Article

C2 - 28985469

AN - SCOPUS:85033370647

VL - 11

SP - 10135

EP - 10146

JO - ACS Nano

JF - ACS Nano

SN - 1936-0851

IS - 10

ER -