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.

中文翻译：

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黑色素瘤中有缺陷的自然杀伤细胞：NKG2D 在发病机制和免疫治疗中的作用。

黑色素瘤是最具侵袭性和最致命的皮肤癌形式，其预后非常差。尽管早期发现对许多治疗有反应，但转移性黑色素瘤对大多数治疗无效。在美国，皮肤黑色素瘤是男性第五种最常见的癌症，女性第六种。目前的治疗方式，取决于癌症分期，主要包括手术切除、化疗、辅助治疗、靶向治疗和免疫治疗。尽管治疗选择范围广泛且反应率稳步提高，但大部分接受治疗的患者会复发并对进一步治疗产生抗药性。免疫疗法临床前和临床试验中的一种新方法是使自然杀伤 (NK) 细胞适应耐药癌细胞。NK 细胞可以杀死多种癌细胞类型以及癌症干细胞，同时保持正常细胞完整。在皮肤黑色素瘤中，与大多数癌症一样，肿瘤微环境 (TME) 中的 NK 细胞功能受损。NK细胞缺陷的原因有几个，其中之一是激活受体NKG2D的失调。这是调节细胞毒活性、细胞因子产生和调节在 NK 细胞和其他淋巴细胞上表达的其他受体的主要受体。癌症模型中的缺陷 NK 细胞与肿瘤生长和转移有关。在这篇综述中，我们讨论了 NK 细胞及其表型变异在皮肤黑色素瘤中的作用。使用生物信息学，我们进一步分析了 NKG2D 的表达，证实了其在皮肤黑色素瘤患者中的低转录水平。此外，我们发现癌症干细胞的 CD133 亚群表达低水平的 NKG2D。基于这些发现，我们讨论了可用于上调患者 NK 细胞中 NKG2D 并恢复其抗黑色素瘤作用的潜在治疗方法，从而导致肿瘤消退和延长生存期。