Israel is fortunate to enjoy sunny days most of the year, but a downside is that overexposure to and lack of protection from its ultraviolet rays can cause melanoma – the most serious and deadliest kind of skin cancer, which develops from pigment-producing cells called melanocytes that give skin its color.
Melanoma typically starts on skin that’s often exposed to the sun, such as the arms, back, and face. It can form in the eyes. Rarely, it can happen inside the body, such as in the nose or throat. Tanning beds are also responsible for the development of the malignancy.
Although it can appear anywhere – including palms, soles, or under nails – the major signs involve changes in moles or new spots with irregular shapes, borders, colors, or slowly developing bleeding or itching – so early detection is crucial as it’s more likely to spread than other skin cancers. Treatment usually involves surgery, potentially followed by immunotherapy, chemotherapy, or radiation if it has spread.
Although Israel has a relatively high incidence of melanoma compared to many countries – partly due to frequent sun exposure (intentional when getting a sunburn) or unintentional, and the prevalence of unprotected fair skin among many residents – the mortality rates are relatively low thanks to early detection and good treatment outcomes.
According to the Health Ministry, there are between 1,700 and 2,000 new diagnoses of this type of skin cancer in Israel every year. Worldwide, there are about 200,000 cases – half of them noninvasive and the rest invasive – with some 8,000 deaths per year.
Research breakthrough with major implications for treatment
But there is good news: A major achievement with far-reaching implications for treating deadly skin cancer has been discovered by Tel Aviv University scientists and colleagues. They discovered a mechanism that allows melanoma cancer cells to paralyze immune cells by secreting extracellular vesicles (EVs), which are tiny, bubble-shaped containers secreted from a given cell. The research team believes that this discovery has far-reaching implications for possible treatments for melanoma.
This dramatic breakthrough was led by Prof. Carmit Levy of the human genetics and computational medicine department at TAU’s Gray Faculty of Medical and Health Sciences – in collaboration with research teams from the Weizmann Institute of Science, the Technion – Israel Institute of Technology, Tel Aviv Sourasky Medical Center, Hadassah-University Medical Center, Rabin Medical Center, Wolfson Medical Center, Sheba Medical Center, the University of Liège (Belgium), Massachusetts General Hospital, Paris-Saclay University, and the University of Zurich.
The study’s findings have just been published in the prestigious journal Cell under the title “HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion.”
Levy, who received a master’s degree in pharmacy and a Ph.D. in biochemistry from the Hebrew University, plus post-doctoral studies at Harvard University, has worked on this project for almost six years. She said in an interview with The Jerusalem Post that it was known that there are immune cells in metastases biopsies of melanoma, but it was not known if and how they could kill the immune cells that attack. “When we made our discovery, it was very surprising to us and everybody in the field,” she said. She and her lab team start working on other cancers as well. “It will take time to reach the bedside, but we are eager to take a step forward.”
In the first stage of the disease, melanocytic cells divide uncontrollably in the epidermis, which is the skin’s outer layer. In the second stage, the cancer cells invade the inner dermis layer and metastasize through the lymphatic and blood systems. In previous studies, Levy discovered that as they grow in the epidermis, melanoma cells secrete large EVs called melanosomes, which penetrate blood vessels and dermal cells, forming a favorable niche for the cancer cells to spread. The new study found that these vesicles also enable cancer cells to paralyze the immune cells that attack them.
“We began studying these vesicles,” Levy told the Post, “and I noticed that on the vesicles membrane there was a ligand – a binding molecule that is supposed to bind to a receptor found only on immune cells called lymphocytes that can kill cancer cells when coming into direct contact with them. I thought that this ligand latches onto lymphocytes that come to kill the melanoma. This was an innovative and odd idea and we started investigating it in the lab.”
When the TAU team collected more evidence that this idea was correct, she contacted colleagues around the world. All came together in a joint effort to decipher the cancer’s behavior – and the achievement is enormous. “We discovered that the cancer essentially fires these vesicles at the immune cells that attack it, disrupting their activity and even killing them.”
Levy’s research focuses on the molecular and cellular mechanisms underlying the development, progression, and microenvironment interactions of melanoma and other cancers, including the role of microRNAs, particularly in melanocyte differentiation and malignant transformation.
She received her doctorate from the Hebrew University of Jerusalem, completed post-doctoral studies at Harvard University, and in 2019 was awarded with the Young Investigator Award by the Society of Melanoma Research Congress.
Levy stressed that the extraordinary discovery is promising, but that more work is needed to translate it into a new therapy. “We still have a great deal of work ahead of us, but it is already clear that this discovery can have far-reaching therapeutic implications,” she said.
“It will enable us to strengthen immune cells so they can withstand the melanoma’s counterattack. In parallel, as we successfully did in a mice model, we can block the molecules that enables vesicles to cling to immune cells, thereby exposing the cancer cells and making them more vulnerable. Either way, this study opens a new door to effective immunotherapeutic intervention. “Our study highlights a novel immune evasion mechanism,” she concluded, “and proposes a therapeutic avenue to enhance tumor immunity.”