Combination of IDO inhibitors and platinum(IV) prodrugs reverses low immune responses to enhance cancer chemotherapy and immunotherapy for osteosarcoma

Dongquan Xiang; Xinli Han; Jianxiong Li; Jiabing Zhang; Haihua Xiao; Ting Li; Xuelin Zhao; Hejian Xiong; Meng Xu; Wenzhi Bi

doi:10.1016/j.mtbio.2023.100675

Combination of IDO inhibitors and platinum(IV) prodrugs reverses low immune responses to enhance cancer chemotherapy and immunotherapy for osteosarcoma

Mater Today Bio. 2023 May 24:20:100675. doi: 10.1016/j.mtbio.2023.100675. eCollection 2023 Jun.

Authors

Dongquan Xiang^{1

2

3}, Xinli Han^{3

4}, Jianxiong Li^{1

2

3}, Jiabing Zhang^{5

6}, Haihua Xiao³, Ting Li⁷, Xuelin Zhao^{1

2}, Hejian Xiong⁸, Meng Xu², Wenzhi Bi²

Affiliations

¹ Medical School of Chinese PLA, Beijing, 100853, PR China.
² Senior Department of Orthopedics, The Fourth Medical Centre, Chinese PLA General Hospital, Beijing, 100048, PR China.
³ Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, PR China.
⁴ School of Medicine, Nankai University, Tianjin, 300074, PR China.
⁵ Xidian University, Xi'an, 710071, PR China.
⁶ Graduate School of Medical School of Chinese PLA Hospital, Beijing, 100853, PR China.
⁷ Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
⁸ Department of Mechanical Engineering, The University of Texas at Dallas, Richardson, TX, 75080, USA.

Abstract

In recent years, immune checkpoint blockades (ICBs) have made great progress in the treatment of cancer. However, most ICBs have not yet been observed to be satisfactory in the treatment of osteosarcoma. Herein, we designed composite nanoparticles (NP-Pt-IDOi) from a reactive oxygen species (ROS) sensitive amphiphilic polymer (PHPM) with thiol-ketal bonds in the main chain to encapsulate a Pt(IV) prodrug (Pt(IV)-C12) and an indoleamine-(2/3)-dioxygenase (IDO) inhibitor (IDOi, NLG919). Once NP-Pt-IDOi enter the cancer cells, the polymeric nanoparticles could dissociate due to the intracellular ROS, and release Pt(IV)-C12 and NLG919. Pt(IV)-C12 induces DNA damage and activates the cGAS-STING pathway, increasing infiltration of CD8⁺ T cells in the tumor microenvironment. In addition, NLG919 inhibits tryptophan metabolism and enhances CD8⁺ T cell activity, ultimately activating anti-tumor immunity and enhancing the anti-tumor effects of platinum-based drugs. NP-Pt-IDOi were shown to have superior anti-cancer activity in vitro and in vivo in mouse models of osteosarcoma, providing a new clinical paradigm for combining chemotherapy with immunotherapy for osteosarcoma.

Keywords: Immunotherapy; Indoleamine-(2/3)-dioxygenase inhibitor; Osteosarcoma; Platinum; STING.