Article

Anti-PD-L1 mediating tumor-targeted codelivery of liposomal irinotecan/JQ1 for chemo-immunotherapy

Authors: Zhi-di He1,2, Meng Zhang1, Yong-hui Wang1,2, Yang He1,2, Hai-rui Wang1,3, Bin-fan Chen1,2, Bin Tu1,2, Si-qi Zhu1,4, Yong-zhuo Huang1,2,5,6
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510450, China
4 Department of Pharmacology, Zhejiang University City College, Hangzhou 310015, China
5 NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China
6 Zhongshan Branch, the Institute of Drug Research and Development, Chinese Academy of Sciences, Zhongshan 528451, China
Correspondence to: Yong-zhuo Huang: yzhuang@simm.ac.cn,
DOI: 10.1038/s41401-020-00570-8
Received: 14 September 2020
Accepted: 1 November 2020
Advance online: 11 December 2020

Abstract

Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8+ T cells and the release of IFN-γ, and the reduced CD4+Foxp3+ regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.
Keywords: tumor-targeted delivery; immunogenic cell death; PD-1/PD-L1 blockade; tumor immune microenvironment; irinotecan; JQ1; immune checkpoint

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