Defective Natural Killer Cells in Melanoma: Role of NKG2D in Pathogenesis and Immunotherapy

Melanoma is the most aggressive and deadliest form of skin cancer, and its prognosis is very poor. Although the early detection is responsive to many treatments, metastatic melanoma is refractory to most of them. In the United States, skin melanoma is the fifth most common type of cancer in men and the sixth in women. Current treatment modalities, depending on the cancer stage, consist primarily of surgical excision, chemotherapy, adjuvant therapy, targeted therapies, and immunotherapy. Despite the wide range of therapeutic options and the steadily increasing response rates, a large subset of the treated patients relapse and develop resistance to further treatments. One novel approach in preclinical and clinical trials in immunotherapy is the adaptation of natural killer (NK) cells against resistant cancer cells. NK cells can kill a variety of cancer cell types, as well as the cancer stem cells, while leaving normal cells intact. In skin melanoma, as in most cancers, NK cells in the tumor microenvironment (TME) are functionally impaired. Several factors underlie the defective cause of NK cells, one of which is the dysregulation of the activating receptor NKG2D. This is the dominant receptor in regulating the cytotoxic activity, cytokine production, and regulation of other receptors expressed on NK cells and other lymphocytes. The defective NK cells in cancer models were associated with tumor growth and metastasis. In this review, we discuss the role of NK cells and their phenotypic variants in skin melanoma. Using bioinformatics, we have further analyzed the expression of NKG2D, confirming its low transcript levels in patients with skin melanoma. Furthermore, we show that the CD133 subset of cancer stem cells expresses low levels of NKG2D. Based on these findings we discuss the potential therapeutic approaches that can be exploited to upregulate NKG2D in patients' NK cells and restore their anti-melanoma effects, resulting in tumor regression and prolonged survival.