1. Academic Validation
  2. Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma

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

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: wang_yan1977@hotmail.com.
  • 12 Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China. Electronic address: lvsq0518@hotmail.com.
  • 13 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. Electronic address: bianxiuwu@263.net.
  • 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: xindongliu@hotmail.com.
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.

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