CNIO research team finds how melanoma deceives the immune system, increasing resistance to immunotherapy

The researchers at CNIO have identified how melanoma redirects the immune system, preventing it from attacking the tumour and transforming it into an ally in cancer development
A key element in this ‘deception’ is MIDKINE, a protein that modifies the function of several components of the immune system. By blocking MIDKINE, the researchers managed to rewire immune cells to resume the attack against the tumour
This finding can lead to the development of optimised immunotherapy, which is only partly effective in some tumours today

The sophisticated human immune system has evolved to become an effective protection system against a great number of diseases, cancer being one of them. The immune system recognises and destroys cancer cells using a monitoring process called immunological surveillance. However, like Dr Jekyll and his alter ego Mr Hyde, the immune system sometimes takes on an alternate personality and favours tumour development instead of destroying cancerous cells. This dual behaviour makes it difficult to detect prognosis indicators and targets for drug development. In fact, one of the big challenges in oncology is the development of better, more effective immunotherapy.

A research team headed by Marisol Soengas, Head of the Melanoma Group at the Spanish National Cancer Research Centre (CNIO), has taken an important step forward, discovering what melanoma cells do to remain undetected by the immune system, which does not attack them and even transforms into an ally. The study, published in Nature Medicine, may have interesting clinical implications and its findings can be applied to other cancer types.

An inside ally for melanoma

In 2017, the researchers in the Melanoma Group at the CNIO found that the MIDKINE protein plays an essential role in melanoma metastasis, so much so that its activation determines the tumour’s potential to metastasise. Actually, melanoma has a very high potential to metastasise early. The CNIO researchers analysed the expression of MIDKINE in a novel animal model and found that higher expression of this protein is related to higher metastasis potential, while blocking MIDKINE inhibits the spread of cancerous cells. Recently, the researchers have taken an important step forward, discovering a new role of the protein in the immune system, which instead of attacking melanoma cells boosts inflammation and promotes melanoma growth.

“Our results help us understand why metastatic melanoma is associated with a poor prognosis and, especially, why some patients do not respond to immunotherapy,” says Marisol Soengas. “We examined databases from six separate studies and found a group of genes associated with MIDKINE expression in patients who do not respond or develop resistance to immunotherapy.”

Dual therapeutic strategy

The observations were tested in animal models: “When we blocked MIDKINE, two important types of immune cells (macrophages and T lymphocytes) began working normally again and attacked the tumour,” says Soengas. “This means that, in treating patients with melanoma, we should take a dual therapeutic approach”. Taking the brakes off an immune response, that is, using immune checkpoint inhibitors, is not enough. “MIDKINE should be inhibited as well, so that the defence system can regain its normal functions”.

“We also studied other tumours, like glioma, lung cancer and kidney cancer,” David Olmeda, co-author of the study, says. “We believe our findings will have a considerable impact in a number of diseases,” he adds.

In the last years, researchers and clinicians have made remarkable efforts to enhance immune cells’ cancer-fighting capabilities. However, even though in some cases immunotherapies are highly successful, this approach needs to be further developed. For example, it has proven ineffective in treating pancreatic cancer, while in the case of melanoma, around 60% of patients respond to treatment.

These differences in tumour response to immunotherapy led to the classification of tumours as hot or cold. Some “hot tumours do not fully respond to treatment, a fact we could not understand before,” says Daniela Cerezo, first author of the study. “Our results contribute to explain the reasons why this is so, and they will help increase the effectiveness of immunotherapy for these tumours.”

The research was funded by the Ministry of Science and Innovation, the Carlos III Health Institute, the Ministry of Health, the Melanoma Research Alliance, Worldwide Cancer Research, the Spanish Association Against Cancer (AECC), BBVA Foundation’s Leonardo Grant for scientific researchers and cultural creators, “la Caixa” Foundation, and H2020-MSCA-Immutrain.

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Reference article

MIDKINE rewires the melanoma microenvironment towards a tolerogenic and immune resistant state. Daniela Cerezo-Wallis et al (Nature Medicine, 2020). DOI: 10.1038/s41591-020-1073-3