A nanounit strategy reverses immune suppression of exosomal PD-L1 and is associated with enhanced ferroptosis

Guohao Wang; Lisi Xie; Bei Li; Wei Sang; Jie Yan; Jie Li; Hao Tian; Wenxi Li; Zhan Zhang; Ye Tian; Yunlu Dai

doi:10.1038/s41467-021-25990-w

A nanounit strategy reverses immune suppression of exosomal PD-L1 and is associated with enhanced ferroptosis

Nat Commun. 2021 Sep 30;12(1):5733. doi: 10.1038/s41467-021-25990-w.

Authors

Guohao Wang^#^{1

2}, Lisi Xie^#^{1

2}, Bei Li^#^{1

2}, Wei Sang^{1

2}, Jie Yan^{1

2}, Jie Li^{1

2}, Hao Tian^{1

2}, Wenxi Li^{1

2}, Zhan Zhang^{1

2}, Ye Tian^{1

2}, Yunlu Dai^{3

4

5}

Affiliations

¹ Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
² Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
³ Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China. yldai@um.edu.mo.
⁴ Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China. yldai@um.edu.mo.
⁵ MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, 999078, China. yldai@um.edu.mo.

^# Contributed equally.

Abstract

In addition to increasing the expression of programmed death-ligand 1 (PD-L1), tumor cells can also secrete exosomal PD-L1 to suppress T cell activity. Emerging evidence has revealed that exosomal PD-L1 resists immune checkpoint blockade, and may contribute to resistance to therapy. In this scenario, suppressing the secretion of tumor-derived exosomes may aid therapy. Here, we develop an assembly of exosome inhibitor (GW4869) and ferroptosis inducer (Fe³⁺) via amphiphilic hyaluronic acid. Cooperation between the two active components in the constructed nanounit induces an anti-tumor immunoresponse to B16F10 melanoma cells and stimulates cytotoxic T lymphocytes and immunological memory. The nanounit enhances the response to PD-L1 checkpoint blockade and may represent a therapeutic strategy for enhancing the response to this therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / pharmacology
Aniline Compounds / therapeutic use
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
B7-H1 Antigen / antagonists & inhibitors
B7-H1 Antigen / metabolism
Benzylidene Compounds / pharmacology
Benzylidene Compounds / therapeutic use
Cell Line, Tumor / transplantation
Drug Carriers / chemistry*
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / immunology
Exosomes / drug effects*
Exosomes / immunology
Exosomes / metabolism
Female
Ferroptosis / drug effects*
Ferroptosis / immunology
Humans
Hyaluronic Acid / chemistry
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immunologic Memory
Lymphocyte Activation / drug effects
Melanoma, Experimental / drug therapy*
Melanoma, Experimental / immunology
Melanoma, Experimental / pathology
Mice
Skin Neoplasms / drug therapy*
Skin Neoplasms / immunology
Skin Neoplasms / pathology
T-Lymphocytes, Cytotoxic / drug effects
T-Lymphocytes, Cytotoxic / immunology
Tumor Escape / drug effects
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology

Substances

Aniline Compounds
B7-H1 Antigen
Benzylidene Compounds
Cd274 protein, mouse
Drug Carriers
GW 4869
Immune Checkpoint Inhibitors
Hyaluronic Acid