In Situ Reprogramming of Tumors for Activating the OX40/OX40 Ligand Checkpoint Pathway and Boosting Antitumor Immunity.

Abstract

OX40 (CD134, TNFRSF4) is a member of the tumor necrosis factor receptor superfamily that can be activated by its cognate ligand OX40L (CD252, TNFSF4) and functions as a pair of T cell costimulatory molecules. The interaction between OX40 and OX40L (OX40/OX40L) plays a critical role in regulating antitumor immunity, including promoting effector T cells expansion and survival, blocking natural regulatory T cells (Treg) activity, and antagonizing inducible Treg generation. However, current OX40 agonists including anti-OX40 monoclonal antibodies (aOX40) have serious side effects after systemic administration, which limits their clinical success and application. Herein, we propose a strategy to reprogram tumor cells into OX40L-expressing "artificial" antigen-presenting cells (APCs) by OX40L plasmid-loaded nanoparticles for boosting antitumor immunity in situ. A novel gene transfection carrier was prepared by a modular hierarchical assembly method, which could efficiently transfect various tumor cells and express OX40L proteins on their surface. These surface-decorated OX40L proteins were proved to stimulate T cell proliferation in vitro while stimulating strong antitumor immune responses in vivo. Importantly, this in situ reprogramming strategy did not induce any toxicity as observed in aOX40 treatment, thus providing a novel method for immune checkpoint stimulator application.

• Authors: Yuxi Gao, Jiayu Zhao, Zichao Huang, Hanqin Zhao, Zhaopei Guo, Sheng Ma, Xing Tang, Wantong Song, Xuesi Chen
• Journal: ACS biomaterials science & engineering (ACS Biomater Sci Eng) Vol. 9 Issue 7 Pg. 4108-4116 (07 10 2023) ISSN: 2373-9878 [Electronic] United States
• PMID: 35653749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• OX40 Ligand
• TNFSF4 protein, human

Topics

• Humans
• OX40 Ligand (genetics, metabolism)
• T-Lymphocytes, Regulatory (metabolism)
• Lymphocyte Activation
• Neoplasms (drug therapy)