Immunologically modified enzyme-responsive micelles regulate the tumor microenvironment for cancer immunotherapy

Zhimin Han; Chunai Gong; Juanjuan Li; Huanhuan Guo; Xinlu Chen; Yangli Jin; Shen Gao; Zongguang Tai

doi:10.1016/j.mtbio.2021.100170

Immunologically modified enzyme-responsive micelles regulate the tumor microenvironment for cancer immunotherapy

Mater Today Bio. 2021 Dec 4:13:100170. doi: 10.1016/j.mtbio.2021.100170. eCollection 2022 Jan.

Authors

Zhimin Han^{1

2}, Chunai Gong³, Juanjuan Li², Huanhuan Guo², Xinlu Chen², Yangli Jin⁴, Shen Gao², Zongguang Tai^{1

2}

Affiliations

¹ Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
² Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
³ Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
⁴ Ningbo Yinzhou No.2 Hospital, Ningbo, 315192, China.

Abstract

Immune checkpoint blockade has been proven to have great therapeutic potential and has revolutionized the treatment of tumors. However, various limitations remain, including the low response rate of exhausted T cells and mutual regulation of multiple immunosuppressive cell types that compromise the effect of single-target therapy. Nano-delivery systems can be used to regulate the tumor immune microenvironment in favor of immunotherapy. In this study, we constructed a polypeptide-based micellar system that encapsulates an aryl hydrocarbon receptor (AhR) inhibitor (CH223191) conjugated to T cell activator anti-CD28. The inhibition of AhR activation downregulates the fraction of immunosuppressive cells and effectively inhibits tumor cell metastasis. In addition, the combination with co-stimulatory antibodies improves T-cell activation and synergistically enhances the antitumor effect of AhR inhibitors. The micellar system developed in this study represents a novel and effective tumor immunotherapy approach.

Keywords: AhR, aryl hydrocarbon receptor; Aryl hydrocarbon receptor; Breast cancer; CMC, critical micelle concentration; Cancer immunotherapy; Co-stimulation; MMP-2, matrix metalloproteinase-2; Micelle; TIME, tumor immune microenvironment; TME, tumor microenvironment.