Combination of STING agonist and CXCR3 antagonist disrupts immune tolerance to overcome anti-PD-L1 resistance in lung adenocarcinoma under oxidative stress

Lingling Zhu; Honglin Gao; Shiqi Huang; Ting Cao; Xiaoqian Zhai; Jia Hu; Ting Wang; Jingsi Dong; Zelong Liu; Jiang Chen; Jiewei Liu; Zhirong Zhang; Qinghua Zhou

doi:10.1016/j.gene.2022.146962

Combination of STING agonist and CXCR3 antagonist disrupts immune tolerance to overcome anti-PD-L1 resistance in lung adenocarcinoma under oxidative stress

Gene. 2023 Jan 30:851:146962. doi: 10.1016/j.gene.2022.146962. Epub 2022 Oct 19.

Authors

Lingling Zhu¹, Honglin Gao², Shiqi Huang³, Ting Cao⁴, Xiaoqian Zhai⁵, Jia Hu⁶, Ting Wang⁷, Jingsi Dong⁸, Zelong Liu⁹, Jiang Chen¹⁰, Jiewei Liu¹¹, Zhirong Zhang¹², Qinghua Zhou¹³

Affiliations

¹ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, College of Polymer Science and Engineering, Sichuan University, Chengdu, China. Electronic address: zhulingling826@wchscu.cn.
² Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, College of Polymer Science and Engineering, Sichuan University, Chengdu, China. Electronic address: 1293486068@qq.com.
³ Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, College of Polymer Science and Engineering, Sichuan University, Chengdu, China. Electronic address: 524873220@qq.com.
⁴ Laboratory of Infectious Diseases and Vaccine, West China Hospital, Sichuan University, Chengdu, China. Electronic address: caoting1022@wchscu.cn.
⁵ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. Electronic address: xiaoqzhai@163.com.
⁶ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. Electronic address: 190172427@qq.com.
⁷ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. Electronic address: wt19811026@163.com.
⁸ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. Electronic address: djs_8923390@163.com.
⁹ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. Electronic address: zliu41@mgh.harvard.edu.
¹⁰ Department of General Surgery, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, China. Electronic address: chenjiang520@zju.edu.cn.
¹¹ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. Electronic address: jerry_ljw@163.com.
¹² Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, College of Polymer Science and Engineering, Sichuan University, Chengdu, China. Electronic address: zrzzl@vip.sina.com.
¹³ Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. Electronic address: prof_qh_zhou@126.com.

PMID: 36272651
DOI: 10.1016/j.gene.2022.146962

Abstract

We investigated the role of the STING1-CXCR3 axis using database data and verified it in a mouse model bearing Lewis lung carcinoma (LLC) cells exposed to hydrogen peroxide (H₂O₂). Mice were treated with STING agonist liposomes (STING-Lip), anti-programmed death-ligand 1 (PD-L1), or STING-Lip + anti-PD-L1. The database data revealed that immune response pathways were enriched in patients with lung adenocarcinoma with upregulated STING1 signaling. Upregulated STING1 signaling was associated with a high abundance of immunoregulatory and effector molecules, cytokines, activated CD8+ T cells, and M1 macrophages in patients with lung adenocarcinoma. In this study, H₂O₂-treated LLC cells promoted an immunosuppressive microenvironment and enhanced tumor growth in mice. STING-Lip inhibited distant, untreated, and H₂O₂-induced LLC growth by activating systemic immunity. STING-Lip + anti-PD-L1 failed to slow distant and untreated LLC growth, whereas STING-Lip + anti-PD-L1 + CXCR3 antagonist inhibited distant tumor growth in mice. The combination of STING1 activation and CXCR3 inhibition may be a novel immunotherapeutic strategy to overcome immune checkpoint inhibitor resistance in lung adenocarcinoma by activating systemic immunity in the tumor microenvironment under oxidative stress.

Keywords: Lewis lung carcinoma; Lung adenocarcinoma; STING1–CXCR3 axis; Tumor microenvironment.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Animals
B7-H1 Antigen
Cell Line, Tumor
Drug Resistance, Neoplasm
Hydrogen Peroxide
Immune Tolerance
Lung Neoplasms* / diet therapy
Membrane Proteins* / agonists
Mice
Oxidative Stress*
Receptors, CXCR3* / antagonists & inhibitors
Tumor Microenvironment

Substances

B7-H1 Antigen
Hydrogen Peroxide
Receptors, CXCR3
Sting1 protein, mouse
Membrane Proteins