Lung cancer is the leading cause of cancer-associated deaths.

One of the most promising ways to treat it is by immunotherapy, a strategy that turns the patient's immune system against the tumour.

In the past twenty years, immunotherapies have been largely based on the degree by which immune cells can infiltrate a lung tumour, which has become a major predictor of the patient's overall prognosis.

The problem is that lung tumours adapt to the attacks and find ways to evade them.

One these ways involves a protein called "Programmed death-ligand 1 (PDL1)", which the tumour cells express on their surface.

When immune cells, e.g. T cells, attack the tumour, PDL1 binds a protein on their own surface appropriately named "programmed cell death protein 1", or PD-1).

This interaction triggers an entire cascade of biological reactions in the immune cells that shuts down their attack machinery and renders them harmless to the tumour.

To deal with this, immunotherapeutic regimens often involve drugs that block PD-1, so as to cut off the tumours evading mechanism.

But, unfortunately, this has not been enough.

What we need is a fuller understanding of the immune circuits that are active in lung cancer; a knowledge that would allow us to optimise and increase the efficiency of current immunotherapies.

Neutrophils help lung tumours hide

To do this, the lab of Etienne Meylan at EPFL used a mouse model of lung cancer to establish what the call an "immune signature" in lung cancer.

The study shows that lung tumours can actually be helped by neutrophils - a type of immune cells that are normally at the first line of attack in infections, allergic reactions, and asthma.

In short, neutrophils contribute to disease progression rather than stop it.

The scientists carried out what is known as "neutrophil depletion", which is a method for studying what happens in a tumour when neutrophil numbers are reduced.

By depleting neutrophils in the mice, the researchers were able to deduce what effects they have on a lung tumour when they are actually present.

Surprisingly, depleting neutrophils caused a profound re-modelling of the immune compartment of the lung tumour, with T cells flooding it.

This means that neutrophils actually help the tumour hide better from T cells - this is referred to as "immune exclusion".

On the contrary, neutrophil depletion sensitised tumours to anti-PD1 immunotherapies.

"Since neutrophils are important in fighting pathogens, neutrophil depletion is unlikely to be used in the clinic," says Meylan.

"Instead, we must concentrate our efforts to understand exactly how neutrophils promote lung tumour development.

This could lead to the identification of drugs that block this specific pro-tumour function of neutrophils."

Neutrophils help lung tumors grow

The data also showed that the presence of neutrophils leads to changes in the function of the tumour's blood vessels.

The changes trigger hypoxia and cause the tumour cells to produce a protein called "Snail".

This is important because Snail is widely known to help cancer cells resist drugs, as well as promote tumour recurrence and metastasis.

The researchers found that Snail in turn increased the secretion of the protein Cxcl2, augmenting neutrophil infiltration.

This creates a positive loop that accelerates the progression of the cancer.

In short, the study shows that neutrophils promote tumour progression and can actually hamper the work of immunotherapy in lung cancer.

The authors describe this as a "vicious cycle" between neutrophils and Snail that ultimately maintains a tumour microenvironment supporting tumour growth.

"Immunotherapies constitute new treatment options with important clinical success for this devastating disease," says Etienne Meylan.

"But in up to two thirds of patients the lung tumours do not respond. We believe our work offers one explanation for this; finding new ways to break the vicious dialogue between neutrophils and tumour cells might impair tumour growth, and also increase the percentage of patients that benefit from immunotherapy."

Source: EPFL | École polytechnique fédérale de Lausanne