Abstract
The low efficiency of currently-used anti-cancer therapies poses a serious challenge, especially in the case of malignant melanoma, a cancer characterized by elevated invasiveness and relatively high mortality rate. The role of the tumor microenvironment in the progression of melanoma and its acquisition of resistance to treatment seems to be the main focus of recent studies. One of the factors that, in normal conditions, aids the organism in its fight against the cancer and, following the malignant transformation, adapts to facilitate the development of the tumor is the immune system. A variety of cell types, i.e., T and B lymphocytes, macrophages, and dendritic and natural killer cells, as well as neutrophils, support the growth and invasiveness of melanoma cells, utilizing a plethora of mechanisms, including secretion of pro-inflammatory molecules, induction of inhibitory receptors expression, or depletion of essential nutrients. This review provides a comprehensive summary of the processes regulated by tumor-associated cells that promote the immune escape of melanoma cells. The described mechanisms offer potential new targets for anti-cancer treatment and should be further studied to improve currently-employed therapies.
Highlights
Until recently, melanoma constituted only 4% of all dermatological cancers; it was responsible for 80% of skin-cancer-related deaths [1]
Monotherapies using small-molecule inhibitors of BRAF V600E have been approved for clinical use in patients with inoperable and metastatic melanoma, followed by the introduction of the BRAF/MEK combination treatment, owing to the quickly emerging resistance based on the reactivation of the mitogen-activated protein kinase (MAPK) pathway in patients treated with single-agent therapy [7,8]
Active natural killer cells (NK) cells participate in the recruitment of antigen-presenting cells (APCs) by the secretion of cytokines, while macrophages, neutrophils and dendritic cells residing in the tumor niche phagocytize dead melanoma cells and present cancer antigens that activate secondary adaptive immune responses based on T cells [10,11]
Summary
Melanoma constituted only 4% of all dermatological cancers; it was responsible for 80% of skin-cancer-related deaths [1]. Even a dual therapeutic strategy may lead to the appearance of resistance driven by a variety of mechanisms It may be associated with the occurrence of subsequent mutations within signaling pathways’ related genes or as a result of adaptive melanoma cell plasticity, which is characterized by transcriptionally distinct phenotypes responsible for a vast intra- and intertumoral heterogeneity of this cancer. Because melanoma is one of the most immunogenic tumors, associated with the formation of a large number of neo-antigens occurring as a result of chromosomal rearrangements or genetic polymorphisms, it has the highest potential to elicit a specific anti-cancer immune response [9] For this reason, immune cells are the target of modern anti-melanoma therapy, directed mainly against programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). This review summarizes the current knowledge concerning the functioning of the immune system during melanoma progression and related therapeutic goals that are or could potentially be used as targets in melanoma treatment
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