The efficiency of immunotherapy against various types of cancers is now improved by EPFL scientists by means of reprogramming tumor blood vessels. These blood vessels are important in delivering oxygen and nutrients for cancer cells' growth.
The laboratory of Michele De Palma at EPFL studied two proteins, namely VEGFA and ANGPT2, which tumours create to induce the growth of new blood vessels. Inhibiting the actions of VEGFA and ANGPT2 may stop the growth of the blood vessels, restrict the supply of oxygen and nutrients, and starve the tumours. To inhibit both VEGFA and ANGPT2, the EPFL team utilized an antibody known as A2V.
Efficiency of A2V
The team examined A2V in investigational models of breast cancer, pancreatic cancer, and melanoma. They discovered that A2V had better therapeutic benefits, while antibodies that inhibit either VEGFA or ANGPT2 had limited efficiency.
Significantly, A2V also blocks metastasis, a condition that often leads to death in cancer patients. Under the control of VEGFA and ANGPT2, tumour blood vessels also gain an abnormal structure that slows down the passage of T cells, therefore minimizing the efficiency of immunotherapy. A2V resulted in the degeneration of many tumour blood vessels; however some persisted after the therapy.
“One fascinating result was that A2V not only degenerated most of the tumour blood vessels, but also reversed the abnormal features of those that had persisted, making them like that of normal blood vessels and more open to the onset of anti-tumoural T cells”, says De Palma.
Certainly, A2V enhanced the “extravasation” of activated T cells into the tumours, a process that is needed to begin an immune response against the tumour. Tumours can escape detection and attacks by guarding immune cells, such as T cells. Tumours achieve this by expressing some proteins, called “immune checkpoint ligands”. Programmed death ligand 1 (PD-L1), which joins PD-1 receptor that is found on the T cells surface, halting them from attacking the tumor. A method to avoid this problem is to use drugs known as checkpoint inhibitors.
These are normally antibodies that identify and attach the immune checkpoint proteins on tumours, hence leaving them permissive to immune attacks. The EPFL researchers discovered that the accumulation of activated T cells around the A2V therapy also stimulated a defensive response: the blood vessels begun to create the checkpoint ligand PD-L1 in an attempt to “blind-sight” the attacking T cells. But, the researchers' team found that it is likely to overcome this hindrance by inhibiting the PD-1 receptor.
Undeniably, an anti-PD-1 antibody highly enhanced the anti-tumoural effects of A2V. “While A2V reversed the tumour blood vessels and helped the arrival of activated T cells, the anti-tumoural T cells happen to quickly repressed upon their extravasation to the tumour microenvironment”, says De Palma.
The study has significant inferences for cancer immunotherapy. “Our work proposes that some anti-angiogenic drugs, namely ANGPT2 inhibitors, have more intense effects on tumours than earlier assumptiont. Additionally targeting the blood vessels, they also facilitate the beginning of anti-tumoural immune responses, which can be supported by immune checkpoint blockade”.
Written by Lax Mariappan, MSc