CD103+CD8+ tissue-resident memory T lymphocytes of melanoma boost anti-tumour immunity and predict immunotherapy outcomes

IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Tianyi Zhang, Junquan Song, Yinlam Li, Kangjie Shen, Jiangying Xuan, Yuan Gao, Lili Lu, Zhi Pang, Lu Wang, Yang Yang, Zixu Gao, Qianrong Hu, Yu Zhu, Chenlu Wei, Shaoluan Zheng, Rongkui Luo, Yingyong Hou, Yuhong Zhou, Chuanyuan Wei, Jianying Gu
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引用次数: 0

Abstract

Background

Immunotherapy has revolutionised melanoma treatment, providing significant clinical benefits by reactivating the anti-tumour immune system. CD8+ tissue-resident memory T lymphocytes (CD8+ TRM) have emerged as crucial mediators of anti-tumour immunity, while their specific role in melanoma remains poorly understood.

Methods

Following CD8+CD45.1+ OT-1 cell adoptive transfer into CD45.2+ mice, we employed magnetic separation to purify and analyse resident memory CD8+ T cells (TRM). We use multiple immunohistochemistry (mIHC) to evaluate the spatial distribution of CD8+ TRM in ZS melanoma cohort. Additionally, the biological function of CD8+ TRM and their impact on anti-tumour immunity are explored using scRNA sequencing and spatial transcriptomics, coupled with in vivo/in vitro experiments. Finally, CD8+ TRM utility as an immunotherapy response predictor is examined across several independent cohorts.

Results

CD8+ TRM demonstrates potent tumour-killing capabilities in melanoma, with CD103 as a distinctive marker. High CD103+CD8+ TRM infiltration in tumour tissues strongly correlates with improved prognosis in melanoma patients. In vivo adoptive transfer of CD103+CD8+ TRM effectively inhibits melanoma progression. Mechanistically, CD103 activates the integrin-dependent PI3K/AKT signalling cascade, promoting both proliferation and anti-tumour effector functions of CD8+ TRM. Notably, CD103+CD8+ TRM preferentially localises within tertiary lymphoid structures (TLS), and its adoptive transfer promotes TLS formation. Clinically, CD103+CD8+ TRM is enriched in immunotherapy-responsive patients and serves as a strong predictor for immune checkpoint blockade (ICB) treatment outcomes.

Conclusions

CD103+ CD8+ TRM cells in melanoma play a key role in the anti-tumour immune process and can also be used as a reliable predictor of immunotherapy efficacy.

Key points

  • CD103 is a reliable marker of tissue-resident memory (TRM) CD8+ T cells in melanoma.

  • CD103+CD8+ TRM cells exhibit potent anti-tumour immune activity.

  • CD103+CD8+ TRM cells predict favourable responses to immunotherapy in melanoma.

Abstract Image

黑色素瘤的CD103+CD8+组织驻留记忆T淋巴细胞增强抗肿瘤免疫并预测免疫治疗结果
背景:免疫疗法已经彻底改变了黑色素瘤的治疗,通过重新激活抗肿瘤免疫系统提供了显著的临床益处。CD8+组织驻留记忆T淋巴细胞(CD8+ TRM)已成为抗肿瘤免疫的重要介质,但其在黑色素瘤中的具体作用仍知之甚少。方法:将CD8+CD45.1+ OT-1细胞过继转移至CD45.2+小鼠体内,采用磁分离法纯化和分析常驻记忆CD8+ T细胞(resident memory CD8+ T cells, TRM)。我们使用多重免疫组织化学(mIHC)来评估CD8+ TRM在ZS黑色素瘤队列中的空间分布。此外,利用scRNA测序和空间转录组学,结合体内/体外实验,探讨CD8+ TRM的生物学功能及其对抗肿瘤免疫的影响。最后,CD8+ TRM作为免疫治疗反应预测因子的效用在几个独立的队列中进行了检验。结果:CD8+ TRM在黑色素瘤中显示出强大的肿瘤杀伤能力,CD103是一种独特的标记物。高CD103+CD8+ TRM浸润与黑色素瘤患者预后改善密切相关。体内过继转移CD103+CD8+ TRM有效抑制黑色素瘤进展。从机制上讲,CD103激活整合素依赖性PI3K/AKT信号级联,促进CD8+ TRM的增殖和抗肿瘤效应功能。值得注意的是,CD103+CD8+ TRM优先定位于三级淋巴结构(TLS),其过继性转移促进了TLS的形成。临床上,CD103+CD8+ TRM在免疫治疗反应性患者中富集,并作为免疫检查点阻断(ICB)治疗结果的有力预测因子。结论:黑色素瘤中CD103+ CD8+ TRM细胞在抗肿瘤免疫过程中发挥关键作用,也可作为免疫治疗疗效的可靠预测指标。重点:CD103是黑色素瘤组织驻留记忆(TRM) CD8+ T细胞的可靠标志物。CD103+CD8+ TRM细胞表现出强大的抗肿瘤免疫活性。CD103+CD8+ TRM细胞预测黑色素瘤免疫治疗的有利反应。
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来源期刊
CiteScore
15.90
自引率
1.90%
发文量
450
审稿时长
4 weeks
期刊介绍: Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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