Endothelial autophagy blockade fosters anti-cancer immunity

Abstract

The discovery of immune checkpoints, consisting of transmembrane ligand-receptor protein pairs that negatively regulate the CD8⁺ T-cell-mediated immune response by antigen-presenting cells (APCs) and by cancer cells, has enabled a fundamental advancement of cancer therapies (Korman et al, 2022). Indeed, harnessing these homeostatic control mechanisms to their own advantage, tumor cells manage to defend themselves from the attack of the immune system, and immune checkpoint blockade (ICB) has proven to be an overwhelmingly successful antitumor therapeutic approach (Korman et al, 2022).

Figure 1. Autophagy inhibition in melanoma blood vessel endothelial cells promotes CD8 + T cell extravasation.

Knock-down of key genes controlling the autophagy process promotes, through STING-dependent and independent mechanisms, the translocation of the pro-inflammatory transcription factor NF-κB into the nucleus of tumor endothelial cells. NF-κB promotes the transcription of genes coding for (1) cytokines and chemokines, which, by activating integrin adhesive receptors, attract lymphocytes; (2) transmembrane proteins such as VCAM1 that act as ligands of leukocyte integrins, such as α4β1. As a consequence, CD8⁺ T cells, which more easily exit tumor blood vessel walls in which endothelial autophagy is inhibited, target and eradicate melanoma cells under the stimulation of the anti-PD-1 immune checkpoint blockade therapy. Created with BioRender.