Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma PMID: 36963400

ADC Targets in Oncology

2026-04-10

Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma

Cancer Cell. 2023 Mar 20;S1535-6108(23)00077-6. doi: 10.1016/j.ccell.2023.03.004.

Haofei Liu ¹ , Qiwen Zhao ² , Leyong Tan ² , Xin Wu ² , Rui Huang ² , Yonglin Zuo ² , Longjuan Chen ² , Jigui Yang ² , Zuo-Xin Zhang ³ , Wenchen Ruan ⁴ , Jiayang Wu ⁴ , Fei He ⁵ , Yiliang Fang ² , Fangyuan Mao ² , Peipei Zhang ² , Xiaoning Zhang ² , Peidi Yin ² , Zexuan Yan ² , Wenwen Xu ² , Huimin Lu ² , Qingrui Li ² , Mei Liang ² , Yanjun Jia ⁶ , Cong Chen ² , Senlin Xu ² , Yu Shi ² , Yi-Fang Ping ² , Guang-Jie Duan ² , Xiao-Hong Yao ² , Zhijian Han ⁷ , Tao Pang ⁸ , Youhong Cui ² , Xia Zhang ² , Bo Zhu ⁹ , Chunjian Qi ¹⁰ , Yan Wang ¹¹ , Sheng-Qing Lv ¹² , Xiu-Wu Bian ¹³ , Xindong Liu ¹⁴

Affiliations

1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jinfeng Laboratory, Chongqing 401329, P.R. China.
2. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.
3. Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
4. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China.
5. Genergy Biotechnology (Shanghai) Co., Ltd, Shanghai 200235, P.R. China.
6. Chongqing International Institute for Immunology, Chongqing 401338, P.R. China.
7. The Key Laboratory of the Digestive System Tumors of Gansu Province, Department of Tumor Center, Lanzhou University Second Hospital, Lanzhou 730030, P.R. China.
8. Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China.
9. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China.
10. Medical Research Center, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou 213003, P.R. China.
11. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. Electronic address: [email protected].
12. Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China. Electronic address: [email protected].
13. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. Electronic address: [email protected].
14. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jinfeng Laboratory, Chongqing 401329, P.R. China. Electronic address: [email protected].

Abstract

Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8⁺ T subsets, as well as cytotoxic CD4⁺ T subsets. Notably, a distinct subpopulation of CD4⁺ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4⁺ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.

Keywords

CyTOF; Glioma immune microenvironment; IL-8- producing T cell; scRNA-seq; tumor immunotherapy.