Cancer cell intrinsic TIM-3 induces glioblastoma progression

Qing Guo; Shuai Shen; Gefei Guan; Chen Zhu; Cunyi Zou; Jingyuan Cao; Wen Cheng; Xiaoyan Xu; Juanhan Yu; Zhiguo Lin; Guoli Wang; Ling Chen; Peng Cheng; Anhua Wu

doi:10.1016/j.isci.2022.105329

Cancer cell intrinsic TIM-3 induces glioblastoma progression

iScience. 2022 Oct 10;25(11):105329. doi: 10.1016/j.isci.2022.105329. eCollection 2022 Nov 18.

Authors

Qing Guo^{1

2}, Shuai Shen^{1

2}, Gefei Guan², Chen Zhu^{1

2}, Cunyi Zou^{1

2}, Jingyuan Cao¹, Wen Cheng^{1

2

3}, Xiaoyan Xu⁴, Juanhan Yu⁵, Zhiguo Lin⁶, Guoli Wang⁷, Ling Chen⁸, Peng Cheng^{2

3}, Anhua Wu^{1

3}

Affiliations

¹ Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
² Department of Neurosurgery, the First Hospital of China Medical University, Shenyang, Liaoning, China.
³ Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China.
⁴ Department of Pathophysiology, College of Basic Medicine Science, China Medical University, Shenyang, Liaoning, China.
⁵ Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China.
⁶ Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
⁷ Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China.
⁸ Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Medical School of Chinese PLA, Institute of Neurosurgery of Chinese PLA, Beijing, China.

Abstract

Glioblastoma (GBM) is identified to share common signal pathways between glioma and immune cells. Here, we find that T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) is one of the most common co-inhibitory immune checkpoints in GBM shared by tumor and non-tumor cells. Glioma cell-intrinsic TIM-3 is involved in not only regulating malignant behaviors of glioma cells but also inducing macrophage migration and transition to anti-inflammatory/pro-tumorigenic phenotype by a TIM-3/interleukin 6 (IL6) signal. In mechanism, as one of the major regulators of IL6, TIM-3 regulates its expression through activating NF-κB. Blocking this feedback loop by Tocilizumab, an IL6R inhibitor, inhibited the above effects and repressed the tumorigenicity of GBM in vivo. Our work identifies glioma cell-intrinsic functions of TIM-3/IL6 signal mediating the crosstalk feedback loop between glioma cells and tumor-associated macrophages (TAMs). Blocking this feedback loop may provide a novel therapeutic strategy for GBM.

Keywords: Cancer; Cell biology; Stem cells research.