1. Academic Validation
  2. Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression

Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression

  • Immunology. 2023 Apr 24. doi: 10.1111/imm.13650.
Shizhen Ding 1 2 Zhijie Lin 2 3 4 Xiaoyuan Zhang 1 Xiaoqing Jia 2 Hualing Li 2 Yi Fu 5 Xuefeng Wang 5 Guoqiang Zhu 4 Guotao Lu 1 Weiming Xiao 1 Weijuan Gong 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
  • 2 Department of Basic Medicine, School of Medicine, Yangzhou University, Yangzhou, Jiangsu, China.
  • 3 Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, Jiangsu, China.
  • 4 Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, China.
  • 5 Department of Basic Medicine, School of Medicine, Soochow University, Suzhou, Jiangsu, China.
Abstract

Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this study, more CD8+ T cells were activated to be effector T cells in ANGPTL4-/- mice. Impaired growth of tumours implanted in 3LL, B16BL6 or MC38 cells and reduced metastasis by B16F10 cells were observed in ANGPTL4-/- mice. Bone marrow (BM) transplantation experiments displayed that deficiency of ANGPTL4 in either host or BM cells promoted CD8+ T cell activation. However, ANGPTL4 deficiency in CD8+ T cells themselves showed more efficient anti-tumour activities. Recombinant ANGPTL4 protein promoted tumour growth in vivo with the less CD8+ T cell infiltration and it directly downregulated CD8+ T cell activation ex vivo. Transcriptome sequencing and metabolism analysis identified that ANGPTL4-/- CD8+ T cells increased glycolysis and decreased oxidative phosphorylation, which was dependent on the PKCζ-LKB1-AMPK-mTOR signalling axis. Reverse correlation of elevated ANGPTL4 levels in sera and tumour tissues with activated CD8+ T cells in the peripheral blood was displayed in patients with colorectal Cancer. These results demonstrated that ANGPTL4 decreased immune surveillance in tumour progression by playing an immune-modulatory role on CD8+ T cells via metabolic reprogramming. Efficient blockade of ANGPTL4 expression in tumour patients would generate an effective anti-tumour effect mediated by CD8+ T cells.

Keywords

ANGPTL4; CD8; T cell; metabolism; tumour.

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