The evolution of the refined human immune system has turned into an effective defense system against several diseases, including cancer. The immune system identifies and kills cancer cells by using a monitoring process known as immunological surveillance.
Marisol Soengas, Head of the CNIO’s Melanoma Group (center), with David Olmeda, co-author of the study, and Daniela Cerezo, first author. Image Credit: A. Garrido, Spanish National Cancer Research Centre.
At times, however, like Dr Jekyll and his friend Mr Hyde, the immune system assumes an alternate personality and promotes the development of tumors rather than killing the cancerous cells.
Such a dual behavior makes it complicated to identify prognosis indicators and targets for drug development. One of the major challenges in oncology is the development of optimized, more effective immunotherapy.
Led by Marisol Soengas, Head of the Melanoma Group at the Spanish National Cancer Research Centre (CNIO), a research group has taken a significant step ahead in identifying what melanoma cells do to stay unnoticed by the immune system, which does not fight them and even changes into an ally. The study was published in the Nature Medicine journal and could have intriguing clinical implications. The findings can be applied even to other types of cancer.
An inside ally for melanoma
In the year 2017, scientists from the Melanoma Group at the CNIO discovered that the MIDKINE protein plays a crucial role in metastasis of melanoma, to such an extent that its activation governs the ability of tumors to undergo metastasis. In fact, melanoma has a higher ability to metastasize early.
The CNIO team examined the expression of MIDKINE in a new animal model and identified that higher expression of this protein is associated with higher metastasis potential while blocking MIDKINE prevents the spread of cancerous cells.
The team has now taken a significant step forward, identifying a new function of the protein in the immune system, which, rather than attacking melanoma cells, promotes melanoma growth and inflammation.
Our results help us understand why metastatic melanoma is associated with a poor prognosis and, especially, why some patients do not respond to immunotherapy. 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.”
Marisol Soengas, Head of the Melanoma Group, Spanish National Cancer Research Centre
Dual therapeutic strategy
The observations were examined in animal models. Soengas stated, “When we blocked MIDKINE, two important types of immune cells (macrophages and T lymphocytes) began working normally again and attacked the tumor. This means that, in treating patients with melanoma, we should take a dual therapeutic approach.”
It is not sufficient to take the brakes off an immune response, that is, to use immune checkpoint inhibitors. Soengas added, “MIDKINE should be inhibited as well so that the defense system can regain its normal functions.”
We also studied other tumours, like glioma, lung cancer and kidney cancer. We believe our findings will have a considerable impact in a number of diseases.”
David Olmeda, Study Co-author, Spanish National Cancer Research Centre
In previous years, scientists and clinicians have made outstanding efforts to improve the cancer-fighting potential of immune cells. Although immunotherapies are highly successful in certain cases, this method needs to be developed further. For instance, it is ineffective in treating pancreatic cancer, whereas in the case of melanoma, about 60% of patients respond to treatment.
These variations in tumor response to immunotherapy led to the classification of tumors as cold or hot. Cerezo explained that certain “hot tumors do not fully respond to treatment, a fact we could not understand before.”
Our results contribute to explain the reasons why this is so, and they will help increase the effectiveness of immunotherapy for these tumours.”
Daniela Cerezo, Study First Author, Spanish National Cancer Research Centre
Cerezo-Wallis, D., et al. (2020) Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nature Medicine. doi.org/10.1038/s41591-020-1073-3.