Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.

Autophagy is a well-conserved intracellular catabolic pathway maintaining cellular homeostasis and is governed by various autophagy-related genes (Atg). Defects in autophagy result in various human pathologies such as cancer. Autophagy has a complex role in cancer, where it functions as a tumor suppressor at the initial stage of tumor initiation but in later stages becomes a cancer cell hijacked mechanism to support further tumor progression.

Various therapeutic strategies such as surgery, systemic therapy, and radiotherapy are used in cancer treatment of various tumor types in different disease stages. A particular example of systemic therapy is immunotherapy, a strategy where components of the immune system are (re)activated to elicit an antitumor immune response. Immune checkpoint blockers (ICB) are agents that reinvigorate immune responses against cancer cells, by boosting cytotoxic T-lymphocytes’ antitumor response. The usage of ICB and the number of approved indications for their use is vastly increasing but their efficacy is not optimal and many patients do not respond, urging for strategies to further improve their efficacy. In the TME, TEC usually possess a poor inflammatory phenotype and act as a barrier between circulating immune cells and the tumor parenchyma, limiting cytotoxic T-cell infiltration.

Autophagy is generally increased in the TME and has a potent anti-inflammatory function, but whether it sustains the anergic phenotype of the TEC is not known.

In this study, we show that autophagy ablation specific in EC by Atg5 knockout increased the inflammatory signature of TEC in a murine melanoma model. This was hallmarked by increased NF-κB pathway-related gene expression resulting in an inflammatory TEC phenotype leading to increased infiltration and activity of cytotoxic CD8+ lymphocytes in the TME leading to tumor response. Importantly, also response to ICB treatment was improved. These findings identify TEC autophagy as a vascular immune checkpoint, an element to be further investigated in future strategies to potentially improve ICB efficacy.