HOW MELANOMA MANIPULATES ITS WAY TO METASTASIS

A growth factor secreted by melanoma cells makes the immune system ignore metastasis

Certain cancers can take control of elements of the body’s immune system, tricking immune cells into favouring the growth of cancer cells rather than attacking and destroying them. The deadliness of melanoma comes from its ability to metastasize rapidly to other organs if it is not treated early, and a new study indicates this process may involve manipulation of the immune system.

A certain proportion of melanoma patients do not respond to immune checkpoint blockade therapy, suggesting that their immune system may be hijacked by melanoma cells. Now, María Soengas and her colleagues at the Spanish National Cancer Research Center (CNIO) in Madrid, Spain, have shown that a growth factor protein called midkine (MDK), which is secreted by melanoma cells, manipulates the immune system

The 3D structure of a melanoma cell. Midkine, which is secreted by melanoma cells and linked with immunotherapy resistance, trains immune cells to turn a blind eye to cancer spread.

microenvironment. This causes immune cells to ignore the cancer threat and allow melanoma to spread.

The team had previously shown that midkine plays multiple roles in metastasis, not just in melanoma but also in other tumours, including gastric and liver cancer. In their latest study, the researchers conducted RNA-sequencing and proteomics analyses of patient biopsy samples to examine how midkine affects gene expression profiles. In addition to showing that patients with a poor prognosis had high levels of midkine expression, the researchers identified a suite of genes affected by changes in midkine levels.

Soengas and her team then turned to mouse models of melanoma to further investigate midkine and its mechanism of action. The team found that high levels of midkine secretion by melanoma cells create an inflamed microenvironment enriched in cytokines (proinflammatory proteins) and other tumourigenic molecules. This environment makes immune cells such as macrophages and T cells ignore the cancer cells, creating a suppressed immune microenvironment that favours metastasis.

Mice with high midkine expression were more likely to suffer metastasis and to be resistant to immune checkpoint blockade therapies. When the team blocked midkine expression, macrophages and T cells began to function normally again, attacking and killing the melanoma cells and reducing cancer spread. The team identified several midkine-related genes that were linked to high midkine expression levels, and these could provide valuable biomarkers to identify patients less likely to respond to immunotherapies.

As they wrote in their Nature Medicine paper, “this data not only links MDK signalling to poor prognosis and sets the proof of principle for dual MDK-ICB [midkine-immune checkpoint blockade] inhibition in melanoma, but also serves as a platform for future studies in other tumours and inflammatory diseases.” Based on this, the researchers believe that treating metastatic melanoma with a dual therapy that targets midkine and the immune checkpoint blockade could dramatically improve patient chances of survival.

Cerezo-Wallis, D. et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nature Medicine26 1865-1877 (2020).