New publication explores how tumours can direct blood vessels to avoid rejection by the immune system

A notable review paper on biological aspects of cancer therapy was recently published in Science Immunology, with major contributions from Sunnybrook Research Institute (SRI) Senior Scientist Dr. Robert Kerbel and postdoctoral research associate Dr. Kabir Khan.

The paper, entitled 'Tumors resurrect an embryonic vascular program to escape immunity'  focuses on the idea that both cancer cells and certain normal cells inside tumours, acting in a similar way to cells in a growing fetus, are able to evade the body’s usual immune response. It may explain at the molecular level a new way by which cancer drugs designed to boost immunity are more effective when used in combination with drugs that block new blood vessel growth.

“Immunotherapy is in many ways revolutionizing – in an almost unprecedented way – the treatment of cancer,” says Dr. Kerbel, “but many patients don’t initially respond, or eventually stop responding.” There is an intensive effort around the world in both academia and industry, he adds, to try and figure out why.

During a normal immune response, proteins called immune checkpoints act to regulate or suppress an 'over-active' immune system, for example to prevent harmful autoimmune reactions. These mechanisms can be present in tumours, resulting in suppression of tumour immunity. Many of the new immunotherapy drugs include antibodies that block these immune checkpoints. There are now eight immune checkpoint antibody drugs approved for the treatment of various types of cancer.

Cancer researchers have known for some time that immunotherapy, especially using immune checkpoint antibodies, is improved when combined with a drug that targets a potent growth factor that causes angiogenesis (new blood vessel formation) in cancer cells. The growth factor is called vascular endothelial cell growth factor (VEGF). In the last 15 or so years, it has been established that not only can VEGF cause new blood vessel formation in cancer cells, but it can also act to locally suppress the immune system within tumours in cancer patients. This topic was previously covered in detail by Khan and Kerbel. Dr. Kerbel’s lab at Sunnybrook has worked on VEGF and anti-angiogenic drugs for over 25 years.

Over the last year or so, a number of pivotal large randomized controlled phase III clinical trials have shown that combining an anti-angiogenic drug that targets VEGF with an immune checkpoint antibody can increase survival in advanced disease cancer patients. Five such combinations have been approved by the FDA in the past few years. Examples include drugs to treat hepatocellular carcinoma (a form of liver cancer) and renal cell carcinoma (a form of kidney cancer).

But answering the question of exactly why and how this combination works has generated many theories. Enter Dr. Kerbel’s collaborators Dr. Arjan Griffioen, director of an angiogenesis research centre at Amsterdam UMC, The Netherlands, and Dr. Else Huijbers, a research associate at Amsterdam UMC. They have been working on a theory that may help explain aspects of the puzzle.

“The theory,” says Dr. Kerbel, “relates to another completely different immunological phenomenon, namely, why a growing fetus is protected against immunity during pregnancy.” Because half the genes and thus half the proteins the fetus expresses are inherited from the father and therefore are ‘foreign’, the mother’s immune system should theoretically go into high gear when it recognizes foreign tissue. But it doesn’t.

In both embryonic development and cancer, angiogenesis – a hallmark of growing tissue – needs to occur hand-in-hand with a silencing of the immune system. This means preventing T-cells and other immune cells from infiltrating foreign tissue to fight it off. “One possibility,” says Dr. Khan, “is that endothelial cells lining the blood vessel walls in a placenta, fetus or tumour can suppress immune cell entry and activity by fine tuning the expression of certain proteins on the cell surface. One example is adhesion molecules, which help bind cells to other cells. A lack of adhesiveness for the immune cells can result in compromised immunity.”

Dr. Griffioen and his group discovered that new, growing blood vessels induced by VEGF in many cases in adult tumours can ‘resurrect’ (bring back) the pattern of expression of adhesion and other molecules that are expressed during early embryonic development and use this pattern as a way of preventing the T immune cells from invading tumours.

Another reason why this is interesting, notes Dr. Kerbel, is that it has long been known that cancer cells per se are capable of switching on genes that encode various proteins associated with early embryonic development, some of which can contribute to tumour growth and metastatic spread. The findings summarised in the Science Immunology paper highlight that this phenomenon can be extended to certain normal cells populating tumours, such as endothelial cells.

This research summary, with major contributions from Drs. Kerbel and Khan from SRI, may help explain a critical question in cancer therapy: why using a drug that blocks the function of potent growth factor VEGF can reverse the fetal-like response of adult tumour blood vessels – and thus sometimes make immune therapy more effective.