How one DNA mutation in breast cancer hijacks the immune system

10 jul 2019 17:21

One defective gene in breast tumour cells can promote metastases elsewhere in the body by steering the immune system in an undesirable direction. This is the p53 gene, which is deleted or mutated in the tumour cells of nearly 40% of breast cancer patients.

An article about this discovery by the research group of immunologist and tumour biologist Karin de Visser of the Netherlands Cancer Institute and Oncode Institute, was published in the scientific journal Nature on July 31.

‘We were quite surprised that a single gene not only regulates processes within the cell but also has such a dominant effect on the immune system throughout the body,' says researcher Max Wellenstein, first author of the Nature publication.

Research leader Karin de Visser: ‘Our study shows that the genetic make-up of tumours has a major impact on the immune system and on the spread of breast cancer. These insights lay the foundation for the future development of new forms of immunotherapy that focus on the DNA code of tumours of individual breast cancer patients.’

Max D. Wellenstein et al., ‘Loss of p53 triggers Wnt-dependent systemic inflammation to drive metastasis of breast cancer’, Nature, 31 July 2019. DOI: 10.1038/s41586-019-1450-6.

 

Systemic inflammation and metastases
Cancer-associated systemic inflammation, which makes patients feel ill and run a fever, is generally not a good sign for the course of the disease and is associated with metastases. Metastatic cancer is virtually never curable. But how is that inflammatory response related to the primary tumour itself?

High neutrophil levels
For a number of years, it has been known that patients with metastases have relatively high circulating neutrophil levels: immune cells that "eat" foreign invaders such as bacteria. An increase in neutrophils is part of a normal systemic inflammatory response. In cancer, however, those neutrophils turn against their allies in the immune system: the tumour-cell-destroying T cells.

In 2015, Karin de Visser's research group already demonstrated that some breast tumours mobilise neutrophils outside the tumour in the patient's body via a chain reaction of signal molecules. These neutrophils were subsequently found to promote the spread of breast tumours by counteracting tumour-killing T cells. Inhibiting neutrophils, as is also done for inflammatory diseases such as rheumatism, may, therefore, be a way to prevent metastases.

Two unsolved questions
But two major questions remained in 2015. The first was: how do tumour cells mobilise neutrophils elsewhere in the body? Where and how does the chain reaction that leads to metastasis start in the tumour cell? The second question, by extension, was: why do some breast tumours mobilise neutrophils that stimulate metastatic behaviour, while others do not?

Research leader Karin de Visser: "If we understand that, we can use those insights to identify patients who might benefit from the inhibition of neutrophils. We could also develop new strategies to redirect tumour-stimulating interactions between cancer cells and immune systems to tumour-inhibiting interactions."

P53
In this new study, the researchers show that the source of the entire chain reaction is one missing or defective gene in the tumour cell. That gene is p53: an extremely important gene and an old acquaintance of cancer researchers because, when it's working properly, it protects against unrestrained cell growth. The gene now appears to have a much broader impact.

In a unique set of 16 different mouse models with all possible forms of breast cancer, Wellenstein, in collaboration with Jos Jonkers' research group, discovered that all mice that suffered from an inflammatory reaction in the blood had one thing in common: the absence of the p53 gene. This excited the researchers, as almost 40% of breast cancer patients have a defective p53 gene in their cancer cells.

Only tumour cells that lack this gene inform their environment via signaling molecules (Wnt signalling) that there is damage, and then trigger an inflammatory response in the blood, which eventually leads to metastases elsewhere in the body. In mouse models with p53-deficient tumours, inhibiting these signal substances prevents the hijacking of the neutrophils and also inhibits the metastasis process.

These new insights lay the foundation for the future development of new forms of immunotherapy that focus on the DNA code of tumours of individual breast cancer patients.

Links:

  • The 2015 Nature paper by the Karin de Visser group: ‘IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis’.
  • News release 2015: ‘How immune cells facilitate the spread of breast cancer’
  • Clinical background article: ‘Cancer-related inflammation and treatment effectiveness’ (Lancet Oncology 2014)