Clinical and molecular overview of immunotherapeutic approaches for malignant skin melanoma: Past, present and future

Melanomas are malignant tumors formed by the uncontrolled proliferation of atypical and genetically mutated melanocytes (Chopra et al., 2020), which are melanin-producing cells, the main photo-protective pigment naturally produced against the genotoxic effects of ultraviolet irradiation (UV). These cells are found in various tissues, including the skin, eyes, hair, and gastrointestinal tract. Abnormalities in melanocytes can lead to the development of melanoma, the etiology of which mainly relies on greater exposure of cutaneous tissue to UV irradiation (Jenkins and Fisher, 2020). Evidence from site-specific analyses indicates a higher density of melanocytes on the face, neck, back, and shoulders, which are also the most exposed areas to UV solar radiation (Purim et al., 2020).

Globally, a progressive increase over the past decades in the incidence of melanomas, varying according to age, sex, skin color, and geographic location (Olsen et al., 2015), has been documented. Between 2008 and 2018, there was an increase in the number of cases and in the number of deaths by 44% and 32%, respectively. Also, the incidence and mortality from skin melanoma are higher among males, who are 10% more likely to develop the disease and 4% more likely to die from melanoma than females. It is estimated that by the year 2025, there will be an increase of approximately 20% in the number of individuals diagnosed and in the number of deaths related to melanoma. By the year 2040, the predictions are even worse, indicating that about 500,000 individuals will be diagnosed with skin melanoma, thus representing a total increase of 62% in the number of cases and 72% in mortality associated with melanoma (Melanoma, 2020).

Melanoma is a multifactorial disease, resulting from the interaction between genetic and environmental factors, aside from the crosstalk between keratinocytes and melanocytes. The molecules produced by keratinocytes act on specific melanocyte receptors and control key processes in the development of these cells, including proliferation, differentiation, dendritogenesis and melanogenesis in the epidermis and hair follicles (Hirobe, 2014). Disorders in these signaling pathways may lead to the transformation of regular melanocytes into neoplastic melanocytes, which are able to escape from the regulatory mechanisms promoted by keratinocytes. Ultimately, these altered cells are marked by increased proliferation and the subsequent formation of melanocytic nevi. These structures are benign atypical lesions formed by clusters of melanocytes that can evolve into dysplastic nevi, which eventually lead to the formation of melanoma. However, this process is not linear, and it can rapidly progress to the malignant form without being precluded by benign neoformations (Meyle and Guldberg, 2009, Goldstein and Tucker, 2013).

Various genes regulating the main biological processes of melanocytes can undergo modifications and mutations during melanoma oncogenesis. The proto-oncogene B-Raf, serine/threonine kinase (BRAF) is a key gene in this process and is detected in about 50% of all cutaneous melanomas (Schummer et al., 2020). Through the MAPK / ERK signaling cascade (or via Ras-Raf-MEK-ERK), the mutated BRAF activates RAS (GTPase switch protein) in an unregulated manner and independently from RTK (tyrosine kinase receptor) binding, thus leading to the activation of the MEK/ERK pathway. Ultimately, this process compromises the mechanisms involved in the control of cell proliferation. The mutation usually occurs at codon 600 of the BRAF oncogene as a result of the exchange of a single nucleotide. In general, 90% of melanomas in this group are related to the BRAFV600E mutation, characterized by the replacement of valine by glutamic acid. Other cases of melanoma with BRAF mutations are associated with the BRAFV600K mutation in which valine is replaced by lysine, and less frequently, with the BRAFV600D and BRAFV600R mutations. BRAF mutations, and their participation in the development of melanoma, suggest a central role in the pathogenesis of the disease as well as a significant association with melanocytic nevi (Sun et al., 2020). Given its high frequency in melanoma, this gene is extremely important in stratifying patients and represents a molecular marker widely used in defining the type of clinical and therapeutic approach to which the patient should be submitted.

Familial melanoma represents the occurrence of melanoma in family groups, either by inherited mutation, common environmental exposure or both. One of the genes frequently associated with this type of melanoma is the cyclin-dependent kinase inhibitor 2 A (CDKN2A), which is involved in the control of cell cycle and encodes two main proteins. One of them is the tumor suppressor protein p16INK4A, a specific inhibitor of the cyclin-dependent kinases (CDK4 and CDK6), which stimulate the progression from G1 to the S phase of the cell cycle. However, the interaction of p16 with these proteins inhibits the phosphorylation of the retinoblastoma protein (pRB), which arrests the cell cycle at the G1 phase (Villacañas et al., 2012, Sherr et al., 2016). The second protein is the alternate reading frame (p14ARF), which has a key inhibitory effect on complexes formed from CDK and other molecules such as the intranuclear protein Cyclin D1, which is encoded by the oncogene CCND1 (cyclin D1). This p14ARF protein can promote tumor growth and acts as a survival factor for these cells (Pho et al., 2006).

Changes in key genes involved in the melanocyte cell cycle directly impact on the development of cutaneous melanoma. Some of these changes can be cumulative and result from long-term exposure to carcinogenic triggers like UV radiation from natural and artificial sources (Craig et al., 2018, Liu-Smith et al., 2017). Given the high aggressiveness of melanoma, it is critical to consider the evolution of melanoma as a critical factor. It is well known that the longer a skin melanoma progresses, the deeper the lesion grows, and consequently, the worse the prognosis. Because of its progressive and accelerated nature, as well as its high mortality rate, cutaneous melanoma must be detected and diagnosed as soon as possible (Shain and Bastian, 2016).

Therefore, time is an important aspect for estimating prognosis and determining the best therapeutic approach for each patient. If melanoma is detected early, complete surgical resection of the lesion is the gold standard treatment, and associated with improved survival rates. If melanoma is discovered at a later time, in an advanced stage, or has spread to other body parts, a surgical procedure alone will be insufficient, and therapeutic intervention will become more complex, making alternative therapies necessary. Advancements in immunotherapy have provided avenues for investigation and the creation of increasingly efficient and secure methods to treat many tumor forms, including melanoma (Muller et al., 2019).

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