Self-Assembled Immunostimulatory Nanodrug Combined with PD-L1 for Boosting Anti-Tumor Chemoimmunotherapy

Abstract

Induction of antigen-specific immune response by maturing dendritic cells (DCs) is a promising strategy for anti-tumor immunotherapy. However, the immunosuppressive tumor microenvironment (TME) and the ineffective tumor-associated antigen (TAAs) presentation of DCs have hindered the efficacy of immunotherapy. Herein, we developed a immunostimulatory nanodrug by direct self-assembly of cyanine5 labeled CPG oligodeoxynucleotide and doxorubicin (Cy5-CPG/DOX). The introduction of Cy5 into CPG could increase the interaction of Cy5-CPG and DOX, accelerating the formation of Cy5-CPG/DOX nanostructure. In vivo , DOX can effectively downregulate the level of regulatory T cells to reverse and abrogate immunosuppressive. Meanwhile, DOX could induce immunogenic cell death to produce TAAs, which further combined with Cy5-CPG promote the maturation of DCs, improving the TAAs presentation ability of DCs. As a result, the Cy5-CPG/DOX nanodrug could awaken the innate immune system, sensitizing tumors to immune checkpoint inhibitors mediated by the programmed death-ligand 1 (PD-L1) antibody. In this way, the Cy5-CPG/DOX combined with PD-L1 can decrease the exhaustion of cytotoxic T lymphocytes, eliciting a durable systemic anti-tumor immunity to eradicate cancer. Our work establishes a stable approach for constructing immunostimulatory nanodrug, promoting the development of progressive therapeutic systems.

Note:
Funding Information: This research was supported by the National Key R&D Program of China [No. 2018YFA0902600], the National Natural Science Foundation of China [Nos. 22174019, 21775025], the Natural Science Foundation of Fujian [No. 2020J06036], the Fujian Provincial Health Technology Project [2021CXA015], the Young and Middle-aged Backbone Personnel Training Project of Fujian Health and Family Planning Commission [2021GGA016].

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: Animal experiments were executed following the Guide for the Care and Use of Laboratory Animals (Ministry of Science and Technology of China, 2006). They were approved by the Institutional Animal Care and Use Committee of Fujian Medical University.

Keywords: Immunostimulatory, Self-assembly, PD-L1, Chemoimmunotherapy