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Neoantigen-Reactive T Cells: The Driving Force behind Successful Melanoma Immunotherapy

新抗原反應性 T 細胞：成功的黑色素瘤免疫療法背后的驅(qū)動力

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.

癌癥免疫療法是一種革命性的癌癥療法。它利用患者自身的免疫系統(tǒng)來對抗并可能治愈癌癥。免疫療法的第一個重大突破來自成功的黑色素瘤治療臨床試驗。從那時起，研究人員一直專注于了解免疫療法背后的科學，以便其他類型癌癥患者也可以從中受益。主要發(fā)現(xiàn)之一是黑色素瘤患者的 T 細胞可能識別一種特定類型的腫瘤抗原，稱為新抗原，然后殺死呈遞這些新抗原的腫瘤細胞。新抗原主要來自在腫瘤細胞中發(fā)現(xiàn)的 DNA 突變。這些突變被翻譯成突變的蛋白質(zhì)，然后由 T 細胞區(qū)分。在本文中，我們討論了 T 細胞在免疫治療中的關鍵作用。

三角細胞搖瓶

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 [1]. 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 [8]. 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) [9].

由于腫瘤細胞來源于自身，免疫系統(tǒng)很難區(qū)分腫瘤細胞和正常細胞。過去四年的研究揭示了免疫系統(tǒng)如何識別和殺死腫瘤細胞。在這里，我們描述了皮膚黑色素瘤和免疫系統(tǒng)，重點關注新抗原可能為免疫系統(tǒng)識別腫瘤細胞提供獨特機會的方式。

5L高效搖瓶

皮膚黑色素瘤是最常見的黑色素瘤類型 [ 1 ]。它來自黑色素細胞，即皮膚內(nèi)的一小部分細胞。黑色素細胞在黑色素的產(chǎn)生方面高度專業(yè)化——這被稱為黑色素生成——因此是皮膚色素沉著的基線。黑素細胞可能會發(fā)生轉(zhuǎn)化并變成惡性的。這是由于內(nèi)在的遺傳傾向、荷爾蒙調(diào)節(jié)和環(huán)境紫外線 (UV) 暴露 [ 2 , 3 ]。重要的是，黑色素生成和與黑色素生成相關的信號通路可能對黑色素瘤的腫瘤發(fā)生以及治療結果產(chǎn)生強烈影響 [ 4 , 5 , 6 , 7]。此外，黑色素生成過程會產(chǎn)生活性氧、醌和半醌中間體，這可能會產(chǎn)生免疫抑制性腫瘤微環(huán)境 [ 8 ]。另一方面，與黑色素產(chǎn)生相關的蛋白質(zhì)通常在黑色素瘤中高度表達，它們已成為分子診斷和治療的特定目標，包括免疫治療（第 1.5.1 節(jié)）[ 9 ]。

血清培養(yǎng)基瓶

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 [8]. 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療法不斷發(fā)展。過去十年為患者帶來了多種有效且持久的治療選擇。轉(zhuǎn)移性環(huán)境中的有希望的結果導致了輔助和新輔助方法的發(fā)展。隨著其他免疫治療藥物的開發(fā)以及聯(lián)合臨床試驗和新輔助臨床試驗的成熟，黑色素瘤的護理標準以及手術方法和時機可能會再次發(fā)生變化 [ 8 ]。在不久的將來，高度個性化的治療，如 ACT 和新抗原疫苗，可能會為對抗這種疾病提供新的治療選擇（圖 2）。

關鍵詞：immunotherapy,neoantigen,T cell, melanoma,免疫治療,新抗原,T細胞,黑色素瘤

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6061/htm