By: Rochelle McAdam, R.I.O.T Contributor
Melanoma is a type of skin cancer that affects up to 3% of people in their lifetime. When caught early, outcomes for patients with melanomas are very good as the cancer can be removed with a common in-office excision procedure. Left untreated, melanomas can progress quickly and spread all over the body, which is known as metastasis. Fortunately, over the last 15 years the available treatments for metastatic melanoma have expanded significantly, this article will review some of these exciting advancements!
What is melanoma?
Melanomas develop from a type of skin cell that is called melanocytes. Melanocytes are responsible for producing the protein melanin, which establishes the pigment in our skin. Melanin is important because it absorbs ultraviolet (UV) radiation from the sun, thereby protecting our skin cells from the damaging UV rays. Although these cells have an important function for protecting our skin, they are also susceptible to transformation into cancer cells. This occurs when melanocytes acquire genetic mutations that cause them to continuously divide producing more and more mutated melanocytes. Eventually, these cells metastasize by moving into our blood or lymphatic systems and travelling to distant sites where they grow tumours.
A key feature of many cancer cells is their ability to escape our immune system. The human immune system is made up of numerous cell types that protect our body from different types of invaders, such as bacteria, viruses, parasites, fungus and even cancer. Two of the immune cell types that are essential for targeting cancer cells are called antigen presenting cells (APCs) and T cells. APCs live in different organs in our body, their job is to let the other immune cells know when invaders are present. To do this, APCs pick up pieces of cells (called antigens) from the environment and “present” the antigens to T cells. This process is known as sensitization and allows the T cells to recognize the cell from which the antigen came from, the target cell. The T cell will then circulate in the body looking for the target cell. Once found, they bind together which allows the T cell to determine if the target is healthy or cancer. If the T cell recognizes that it is a cancer cell it will initiate its destruction.
A good analogy for this process is crime scene fingerprinting. Forensic investigators (APCs) find fingerprints (antigens) at a crime scene and give them to the police (T cells). The police go out and search for the criminal who left the print behind. They then find the suspect, confirm the fingerprint is a match and if guilty, they then arrest them.
Why does our immune system fail to kill cancer cells?
Some cancer cells can trick T cells into thinking they are normal cells. They do this by expressing proteins on their surface that are known as immune checkpoint molecules. The immune checkpoint molecules bind to partner proteins on T cells which makes the T cells think they are normal cells and not cancer. Immune checkpoint molecules normally function to stop T cells from activating against normal cells in our body, however, the cancer cells adopt this normal cell function for their own gain. To return to our analogy, the criminal avoids arrest by showing a police badge, tricking the police into thinking the criminal is actually one of them!
Melanoma is one of several types of cancer that uses this mechanism to evade the immune system. In the 1990s, researchers discovered that they could block the immune checkpoint interaction between T cells and cancer cells, which allowed the immune system to target these cells again. They did this by introducing proteins in the blood that would directly disrupt the interaction between the immune checkpoint molecule on the cancer cell and the receptor on the T cell. These “blocker” proteins are known as immune checkpoint blockers (ICB), which prevent the cancer cell from tricking the T cells into thinking they are normal, healthy cells.
Figure made with BioRender.
After ICBs were first developed, these drugs underwent more than 10 years of clinical trials in humans before the first ICB was approved by the U.S. Food and Drug Administration in 2011. Since then, more research has focused on understanding the mechanisms by which cancer cells dampen T cell cancer-killing functions. More ICBs have been developed, which has led to longer survival times for many patients. What’s more, given that different ICBs work through slightly different mechanisms, multiple ICBs can be used together which can enhance their effect. Unfortunately, the use of ICBs for the treatment of melanoma is generally not curative therapy and they come with many side effects. That being said, the discovery of ICBs shed light on a new way of targeting metastatic cancer, which has broadened the tools available to treat this devastating disease.
Despite the amazing advances in immunotherapy for melanoma treatment, the best way to treat melanoma is to catch it early and remove it. It can be helpful to perform self-screening of moles to monitor for skin lesions that could be melanoma. Talk to your family doctor about concerning features of moles and how to track moles over time. Further, the Canadian Cancer Society webpage on melanoma has more information about self-screening, you can check out their resources at this link.
Rochelle McAdam is currently a medical student at the University of Toronto. She previously completed a PhD studying the electrical properties of brain tumour cells at SickKids Research Institute. She has been a R.I.O.T. volunteer for over 5 years and is passionate about enhancing scientific literacy among the general population through blog writing and educational presentations.
References
Huang, A.C. and Zappasodi, R. A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance. Nat. Immunol. (2022)
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271,1734–1736 (1996).
Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Wolchok, J. D. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J. Clin. Oncol. 40, 127–137 (2021).
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