免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
克服黑色素瘤 T 细胞耗竭的免疫肿瘤学策略
英文原题：Immuno-oncology approaches to overcome T cell exhaustion in melanoma.
查看英文原题
Immuno-oncology approaches to overcome T cell exhaustion in melanoma.
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中文摘要
黑色素瘤是一种高度侵袭性的皮肤癌，免疫治疗，尤其是T细胞免疫调节方面，已取得显著进展。T细胞是抗肿瘤免疫应答的重要组成部分，能够显著影响黑色素瘤治疗效果。本综述评估不同T细胞亚群（CD8⁺、CD4⁺和调节性T细胞[Treg]）在黑色素瘤免疫中的作用。CD8⁺ T细胞是重要效应细胞，主要识别并杀伤肿瘤细胞；然而，慢性抗原暴露及PD-1和CTLA-4等免疫检查点通路功能异常可导致其耗竭和功能障碍。CD4⁺ T细胞又称辅助性T细胞，在协调促肿瘤和抗肿瘤免疫应答方面发挥关键作用。与效应T细胞不同，肿瘤微环境中常见的Treg可通过免疫抑制限制T细胞活性。本综述还考察T细胞耗竭机制、肿瘤微环境中T细胞亚群的代谢重编程，以及CTLA-4、PD-1等免疫检查点通路在T细胞免疫中的作用。过继细胞疗法（ACT），尤其是TIL（肿瘤浸润淋巴细胞）疗法和CAR-T 细胞疗法，已显示出重振T细胞并改善临床结局的能力，但耐药机制和抑制性肿瘤微环境仍构成障碍。未来研究将聚焦联合治疗、代谢干预和新型工程技术，以克服T细胞功能耗竭及持久性不足。评估可早期预测疗效和相关毒性的生物标志物，对个体化治疗至关重要。
总之，本综述强调，靶向T细胞耗竭有望提高T细胞疗法疗效并改善黑色素瘤患者结局。
展开英文摘要原文
Melanoma, a highly aggressive type of skin cancer, has undergone incredible developments in immunotherapy, particularly in modulating T-cell immunity. T cells are essential components of the antitumor immune response and can undoubtedly influence the effectiveness of melanoma treatment. This review will evaluate the roles of the different T cell subsets (CD8 + , CD4 + , and Tregs) in melanoma immunity. CD8 + T cells are important effectors, as they primarily recognize and kill tumor cells.
However, CD8+ T cells are often dysfunctional due to exhaustion driven by chronic antigen exposure and dysfunctional immune checkpoint pathways, specifically PD-1 and CTLA-4. On the other hand, CD4 + T cells, also known as T helper cells, play a crucial role in coordinating both pro- and antitumor immune responses. In contrast to T cells, Tregs, which are often present in the tumor microenvironment, lead to immune suppression through their activity, limiting T cell activity.
This review will also examine the mechanisms of T-cell exhaustion, metabolic reprogramming within the tumor microenvironment (TME) of T-cell subsets, and the role of immune checkpoint pathways, such as CTLA-4 and PD-1, in T-cell immunity. Adoptive cell therapies (ACT), specifically Tumor-Infiltrating Lymphocyte (TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy, have shown the ability to rejuvenate T-cells to enhance clinical outcomes.
However, several resistance mechanisms and the suppressive TME presents difficulties. Future efforts will focus on combination therapies, metabolic interventions, and novel engineering techniques to overcome barriers to T-cell function exhaustion and T-cell persistence.
Evaluating biomarkers associated with early prediction for therapeutic benefit and associated toxicity is important for personalizing a particular treatment. Ultimately, this review highlights the potential of targeting T-cell exhaustion to enhance the effectiveness of T-cell-based therapies in improving outcomes for melanoma patients.
论文信息
- 作者
- El-Sehrawy AAMA、Alshahrani MY、Fedwi MM、Ganesan S、Al-Khafaji ZA、Arora V、Pal A、Nayak PP
- 单位
- Department of Internal Medicine, Diabetes, Endocrinology and Metabolism, Mansoura University, Mansoura, Egypt. Electronic address: amaralim799@gmail.com.Egypt
- 文献类型
- 综述 · 非美国政府资助研究
- 期刊
- Seminars in oncology2026 Feb
- 原文标识
- PubMed 41455351 · DOI 10.1016/j.seminoncol.2025.152454