Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.
Jelle VerhoevenKathryn A JacobsFrancesca RizzolloFrancesca LodiYichao HuaJoanna PoźniakAdhithya Narayanan SrinivasanDiede HoubaertGautam ShankarSanket MoreMarco B SchaafNikolina Dubroja LakicMaarten GanneJochen LamoteJohan Van WeyenberghLouis BoonOliver BechterFrancesca BosisioYasuo UchiyamaMathieu Jm BertrandJean Christophe MarineDiether LambrechtsGabriele BergersMadhur AgrawalPatrizia AgostinisPublished in: EMBO molecular medicine (2023)
Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched Inflammatory High /Autophagy Low TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8 + T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.
Keyphrases
- oxidative stress
- signaling pathway
- cell death
- endoplasmic reticulum stress
- endothelial cells
- single cell
- skin cancer
- rna seq
- end stage renal disease
- poor prognosis
- gene expression
- anti inflammatory
- chronic kidney disease
- pi k akt
- high throughput
- dendritic cells
- ejection fraction
- genome wide
- newly diagnosed
- long non coding rna
- dna methylation
- regulatory t cells
- peritoneal dialysis
- vascular endothelial growth factor
- high fat diet induced
- binding protein
- high glucose
- cell proliferation
- type iii