Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

Abstract

Melanoma is one of the most lethal neoplasms of the skin. Despite the revolutionary introduction of immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. Melanoma employs a multitude of mechanisms to subvert the immune system and successfully metastasize to distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression and enter dormant states, eventually leading to metastases at a future time. Immune escape and metastasis have previously been viewed as separate phenomena; however, accumulating evidence is breaking down this dichotomy. Recent research into the progressive mechanisms of melanoma provides evidence that dedifferentiation similar to classical epithelial to mesenchymal transition (EMT), genes involved in neural crest stem cell maintenance, and hypoxia/acidosis, are important factors simultaneously involved in immune escape and metastasis. The likeness between EMT and early dissemination, and differences, also become apparent in these contexts. Detailed knowledge of the mechanisms behind “dual drivers” simultaneously promoting metastatically inclined and immunosuppressive environments can yield novel strategies effective in disabling multiple facets of melanoma progression. Furthermore, understanding progression through these drivers may provide insight towards novel treatments capable of preventing recurrence arising from dormant dissemination or improving immunotherapy outcomes.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…Malignant transformation of melanocytes with further progression to advanced stages, collectively called melanomagenesis, is initiated and driven by environmental, genetic (inheritable), constitutional, and epigenetic factors, as well as by acquired mutations with the accumulation of genomic changes further amplified by local and systemic neuroimmunoendocrine factors affecting progression of the disease [ 1 , 2 , 4 , 6 , 9 , 11 , 12 , 13 , 14 , 30 , 32 , 50 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Since these factors have been discussed in many review articles, we will only provide a brief overview of them.…”

“…The developing resistance to targeted- or immuno-therapy leading to recurrent disease and death of the patient represents a significant challenge. There are different mechanisms underlying this negative phenomenon, including tumor heterogeneity with pre-existing mutations allowing clonal expansion of resistant cells, mutations during therapy and progression of the disease, mutator phenotype, metabolic heterogeneity, and dynamic changes in the tumor microenvironment, to name a few [ 4 , 6 , 25 , 30 , 37 , 74 , 75 , 87 , 130 , 165 , 178 , 179 , 182 , 211 , 218 , 229 , 230 , 231 , 232 , 233 ]. It must be noted that melanoma itself can affect the host response at local and systemic levels through production of neurohormonal regulators (as expected because of the neural crest origin of melanocytes) with immunosuppressive properties [ 3 , 50 , 82 , 234 ], including intermediates of melanogenesis and melanin that would increase resistance to any type of therapy [ 4 , 235 , 236 ].…”

Advancing immunotherapy for melanoma: the critical role of single-cell analysis in identifying predictive biomarkers

“…As melanoma progresses, the acquisition of immune suppression in the environment and changes in endogenous pathways allow for immune escape. The main mechanisms of immune escape in melanoma include immune recognition defects, immune checkpoint receptors, and epithelial-mesenchymal transition (EMT) ( 10 ). Melanoma cells counteract antigen recognition and immune system stimulation through various strategies.…”

Silencing Exosomal circ102927 Inhibits Foot Melanoma Metastasis via Regulating Invasiveness, Epithelial-Mesenchymal Transition and Apoptosis

“… 2 Although immune checkpoint inhibitors and targeted therapies greatly enhance melanoma treatment outcomes, metastatic spread and recurrence remain major challenges. 3 , 4 Acral melanoma, a subtype that occurs in hairless skin tissue, such as the palms of the hands, soles of the feet, or under the fingernails and toes, typically has a poorer prognosis than other melanoma subtypes. This poorer prognosis is often due to delayed diagnosis, which makes acral melanoma more susceptible to metastasis.…”