Neoantigen-Reactive T Cells: The Driving Force behind Successful Melanoma Immunotherapy
新抗原反应性 T 细胞：成功的黑色素瘤免疫疗法背后的驱动力
Cancer immunotherapy is a revolutionary type of cancer therapy. It uses the patient’s own immune system to fight and potentially cure cancer. The first major breakthrough of immunotherapy came from successful clinical trials for melanoma treatments. Since then, researchers have focused on understanding the science behind immunotherapy, so that patients with other types of cancer may also benefit. One of the major findings is that the T cells in melanoma patients may recognize a specific type of tumor antigen, called neoantigens, and then kill tumor cells that present these neoantigens. The neoantigens mainly arise from the DNA mutations found in tumor cells. These mutations are translated into mutated proteins that are then distinguished by T cells. In this article, we discuss the critical role of T cells in immunotherapy, as well as the clinical trials that shaped the treatments for melanoma.
癌症免疫疗法是一种革命性的癌症疗法。它利用患者自身的免疫系统来对抗并可能治愈癌症。免疫疗法的第一个重大突破来自成功的黑色素瘤治疗临床试验。从那时起，研究人员一直专注于了解免疫疗法背后的科学，以便其他类型癌症患者也可以从中受益。主要发现之一是黑色素瘤患者的 T 细胞可能识别一种特定类型的肿瘤抗原，称为新抗原，然后杀死呈递这些新抗原的肿瘤细胞。新抗原主要来自在肿瘤细胞中发现的 DNA 突变。这些突变被翻译成突变的蛋白质，然后由 T 细胞区分。在本文中，我们讨论了 T 细胞在免疫治疗中的关键作用。
1. Cutaneous Melanoma and the Immune System
Because tumor cells arise from the self, it is difficult for the immune system to distinguish between tumor and normal cells. Research in the past four decades has shed light on how the immune system recognizes and kills tumor cells. Here, we describe cutaneous melanoma and the immune system, focusing on the ways in which neoantigens may provide a unique opportunity for the immune system to recognize tumor cells.
1.1. The Tumorigenesis of Cutaneous Melanoma
Cutaneous melanoma is the most common type of melanoma . It arises from melanocytes, a small population of cells within the skin. Melanocytes are highly specialized in the production of melanin—which is called melanogenesis—and thus baseline skin pigmentation. Melanocytes may undergo a transformation and become malignant. This occurs due to intrinsic genetic predisposition, hormonal regulation and environmental ultraviolet (UV) exposure [2,3]. Importantly, melanogenesis and melanogenesis-associated signaling pathways may have a strong influence in the tumorigenesis of melanoma, as well as therapeutic outcomes [4,5,6,7]. Additionally, the process of melanogenesis generates reactive oxygen species, quinone and semiquinone intermediates, which may create an immunosuppressive tumor microenvironment . On the other hand, proteins associated with the melanin production are often highly expressed in melanoma, and they have become specific targets for molecular diagnostics and treatments, including immunotherapy (Section 1.5.1) .
皮肤黑色素瘤是最常见的黑色素瘤类型 [ 1 ]。它来自黑色素细胞，即皮肤内的一小部分细胞。黑色素细胞在黑色素的产生方面高度专业化——这被称为黑色素生成——因此是皮肤色素沉着的基线。黑素细胞可能会发生转化并变成恶性的。这是由于内在的遗传倾向、荷尔蒙调节和环境紫外线 (UV) 暴露 [ 2 , 3 ]。重要的是，黑色素生成和与黑色素生成相关的信号通路可能对黑色素瘤的肿瘤发生以及治疗结果产生强烈影响 [ 4 , 5 , 6 , 7]。此外，黑色素生成过程会产生活性氧、醌和半醌中间体，这可能会产生免疫抑制性肿瘤微环境 [ 8 ]。另一方面，与黑色素产生相关的蛋白质通常在黑色素瘤中高度表达，它们已成为分子诊断和治疗的特定目标，包括免疫治疗（第 1.5.1 节）[ 9 ]。
Immunotherapy for advanced melanoma is constantly evolving. The last decade has brought multiple effective and durable treatment options for patients. Promising results in the metastatic setting led to the development of adjuvant and neoadjuvant approaches. As additional immunotherapy agents are developed and the combination and neoadjuvant clinical trials mature, the standard of care for melanoma and the surgical approaches and timing will likely change yet again . In the near future, highly personalized treatments, such as ACT and neoantigen vaccines, may provide new therapeutic options to combat this disease (Figure 2).
晚期黑色素瘤的免疫疗法不断发展。过去十年为患者带来了多种有效且持久的治疗选择。转移性环境中的有希望的结果导致了辅助和新辅助方法的发展。随着其他免疫治疗药物的开发以及联合临床试验和新辅助临床试验的成熟，黑色素瘤的护理标准以及手术方法和时机可能会再次发生变化 [ 8 ]。在不久的将来，高度个性化的治疗，如 ACT 和新抗原疫苗，可能会为对抗这种疾病提供新的治疗选择（图 2）。
关键词：immunotherapy,neoantigen,T cell, melanoma,免疫治疗,新抗原,T细胞,黑色素瘤