Melanoma: Discovery May Help Improve the Effectiveness of Immunotherapy

American scientists have found a new way to improve the immune system’s ability to fight melanoma of the skin, the deadliest of all skin cancers.


In skin cancers, melanoma is the rarest form (10%) but also the most serious. Unfortunately, its frequency has been steadily increasing for half a century. In some patients, the development of anti-tumor immunotherapies, which use the power of an individual’s immune system to destroy tumors, has revolutionized treatment. Patients with advanced melanoma have been able to survive for years instead of months. For this category of people, treatment only works in 40% of cases.

Today, researchers have taken a major step forward in the fight against melanoma. According to a study published in the journal Nature Communications, scientists at the Sanford Burnham Prebys Medical Discovery Institute have found a new way to strengthen the immune system’s ability to fight cancer.

Scientists have long known that Siah2 is involved in the processes that tumors use to grow. In this case, scientists have used genetically modified mice not to produce the protein and have introduced a BRAF-like melanoma, which occurs in half of all human melanomas. They then noted that in the absence of the Siah2 gene, the melanoma tumors were shrinking with anti-PD-1 therapy, while in the Siah2-bearing mice they were still growing.

A need to find a drug that will block Siah2.

Going further, the scientists found that in the mice without Siah2, the tumors were infiltrated by killer immune cells and lacked the Treg cells, regulatory cells that limit the effectiveness of the immunotherapies currently in use. Thus, the immune system was more effective in eliminating the tumors.

“In our study, mice without the Siah2 gene were able to mount an immune attack against melanoma. In addition, the efficacy of Siah2 in immunotherapy has been demonstrated for tumors  that do not respond to immunotherapy – which were effectively eliminated by blocking PD-1 in the mutant Siah2 mice,” explains Professor Ze’ev Ronai, lead author of the study.

“Although Siah2 is involved in controlling the activities that regulate cancer development, this study provides the first direct evidence of its role in the immune system, i.e. anti-tumor immunity,” he says. Ze’ev Ronai explains: “Our study shows that a PD-1 inhibitor can be used to treat tumors that do not currently respond to this therapy when given to mice without the Siah2 gene, thus providing a means to extend the effectiveness of immunotherapy. These results also justify our efforts to find a drug that blocks Siah2.

“Understanding the basic mechanisms of tumor immunity will ultimately help us improve the effectiveness of immunotherapy,” says Michael Rape, professor of cell and developmental biology at the University of California, Berkeley. This study reveals an important layer in the regulation of key immune cell components that impact the effectiveness of cancer immunotherapy, highlighting the need to develop inhibitors for Tregs, where a Siah2 inhibitor shows promise.

Melanoma can occur in the skin of the breast in 70-80% of cases.

“Our discovery only fuels our sense of urgency to find a drug that inhibits Siah2. Using an array of new approaches should allow us to advance the targeting of Siah2 in both tumors and their microenvironment,” the researchers conclude.

Melanoma can appear in healthy skin in 70-80% of cases, or be the result of the malignant transformation of a mole, hence the importance of regular screening by a dermatologist, because diagnosed early, a melanoma is curable. In case of doubt and if an appointment is not obtained in a short time, one can always resort to the ABCDE rule (for Asymmetric, Border, Color, Diameter and Evolution), a self-diagnostic technique developed by specialists. According to the ABCDE rule, a spot or mole with one of the following characteristics may be suspect: asymmetrical and irregular edges, inconsistent color, increasing or changing diameter.

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