Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA.
Specialization in Systems Biology & Genomics, Department of Life Sciences, School of Sciences, European University Cyprus, 1516, Nicosia, Cyprus; Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, 2713 Doha, Qatar.
Crit Rev Immunol. 2021;41(2):45-76. doi: 10.1615/CritRevImmunol.2021037186.
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.
黑色素瘤是最具侵袭性和致命性的皮肤癌，其预后非常差。尽管早期检测对许多治疗方法都有反应，但转移性黑色素瘤对大多数治疗方法都有抗药性。在美国，皮肤黑色素瘤是男性中第五种最常见的癌症类型，也是女性中的第六种。目前的治疗方法主要取决于癌症的分期，包括手术切除、化疗、辅助治疗、靶向治疗和免疫治疗。尽管有广泛的治疗选择和稳步提高的反应率，但很大一部分接受治疗的患者会复发，并对进一步的治疗产生耐药性。在免疫治疗的临床前和临床试验中，一种新的方法是利用自然杀伤 (NK) 细胞来对抗耐药癌细胞。NK 细胞可以杀死多种癌细胞类型，以及癌症干细胞，同时使正常细胞不受损伤。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 细胞功能缺陷的原因有几个，其中一个是激活受体 NKG2D 的失调。NKG2D 是调节 NK 细胞和其他淋巴细胞表达的细胞毒性活性、细胞因子产生和其他受体调节的主要受体。在癌症模型中，功能缺陷的 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。我们使用生物信息学进一步分析了 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，我们还表明，癌症干细胞的 CD133 亚群表达低水平的 NKG2D。基于这些发现，我们讨论了可以利用的潜在治疗方法，以上调患者 NK 细胞中的 NKG2D，并恢复其抗黑色素瘤作用，从而导致肿瘤消退和延长生存时间。
