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

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.