不适合移植的大 B 细胞淋巴瘤二线使用 axicabtagene ciloleucel：ALYCANTE 最终分析
Second-line axicabtagene ciloleucel in large B-cell lymphoma ineligible for transplantation: ALYCANTE final analysis.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
以 UQCRFS1 为代表的高氧化磷酸化标记弥漫大 B 细胞淋巴瘤中 CD8+TIL（肿瘤浸润淋巴细胞）的耗竭
英文原题：High oxidative phosphorylation represented by UQCRFS1 marks CD8 + tumor-infiltrating lymphocytes exhaustion in diffuse large B-cell lymphoma.
查看英文原题
High oxidative phosphorylation represented by UQCRFS1 marks CD8 + tumor-infiltrating lymphocytes exhaustion in diffuse large B-cell lymphoma.
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研究概要
我们的研究强调了 OXPHOS 活性在 CD8 + TILs 耗竭中的重要性，并提示了其可能的调控机制，这在临床评估中是可行的，并有利于 DLBCL 的新型免疫治疗策略。
研究思路结论见上方概要
背景
代谢改变与CD8+TIL（肿瘤浸润淋巴细胞）（TILs）的耗竭和免疫缺陷密切相关，而在弥漫性大B细胞淋巴瘤（DLBCL）中对此知之甚少。本研究旨在阐明DLBCL中耗竭CD8+TILs代谢改变的意义及其潜在调控机制。
方法
通过单细胞RNA测序（scRNA-seq）评估了DLBCL中耗竭CD8 + TILs的代谢改变。通过scRNA-seq和RNA测序研究了关键代谢通路及其在耗竭CD8 + TILs生物学功能中的意义。通过scRNA-seq、RNA测序、免疫组织化学和RT-qPCR评估了关键代谢通路中的标志基因，及其与耗竭状态、肿瘤微环境（TME）组成、临床病理特征、预后和免疫检查点阻断（ICB）治疗疗效之间的相关性。此外，通过scRNA-seq、RNA测序和体细胞突变分析探讨了与CD8 + TILs耗竭相关的代谢改变所涉及的潜在调控机制。
结果
我们的研究揭示了CD8 + TILs中的代谢异质性，并证明氧化磷酸化（OXPHOS）是CD8 + TILs耗竭的关键通路。高OXPHOS活性表明耗竭CD8 + TILs存在免疫缺陷，UQCRFS1被鉴定为标志基因。高UQCRFS1提示免疫抑制性TME、严重的临床病理特征，包括活化B细胞样亚型、高IPI和PS评分、晚期分期、不良预后以及对ICB治疗的耐药性。此外，DLBCL中MYC相关信号通路和P2RY8突变可能调控耗竭CD8 + TILs中UQCRFS1的表达。
展开英文摘要原文
BACKGROUND
Metabolic alterations are closely associated with the exhaustion and immune deficiency of CD8 + tumor-infiltrating lymphocytes (TILs), while little is known about diffuse large B-cell lymphoma (DLBCL). This study aimed to elucidate the significance of the metabolic alterations in exhausted CD8 + TILs and its underlying regulatory mechanism in DLBCL.
METHODS
The metabolic alterations in exhausted CD8 + TILs in DLBCL were evaluated through single-cell RNA sequencing (scRNA-seq). The crucial metabolic pathway and its significance in the biological function of exhausted CD8 + TILs were investigated by scRNA-seq and RNA sequencing. The marker gene in crucial metabolic pathway, and its correlations between exhaustion status, the tumor microenvironment (TME) composition, clinicopathological characteristics, prognosis, and immune checkpoint blockade (ICB) therapy efficacy were evaluated by scRNA-seq, RNA sequencing, immunohistochemistry, and RT-qPCR. Furthermore, the underlying regulatory mechanism involved in the metabolic alteration related to CD8 + TILs exhaustion was explored through scRNA-seq, RNA sequencing, and somatic mutation analysis.
RESULTS
Our study illustrated the metabolic heterogeneity in CD8 + TILs, and demonstrated that oxidative phosphorylation (OXPHOS) was the crucial pathway in CD8 + TILs exhaustion. The high OXPHOS activity indicated the immune deficiency in exhausted CD8 + TILs, and UQCRFS1 was identified as a marker gene. High UQCRFS1 indicated the immunosuppressive TME, severe clinicopathological characteristics, including activated B-cell-like subtype, high IPI and PS score, advanced stage, dismal prognosis, and resistance to ICB therapy. Furthermore, MYC-related signaling and P2RY8 mutation in DLBCL may regulate the UQCRFS1 expression in exhausted CD8 + TILs.
CONCLUSIONS
Our study highlights the importance of OXPHOS activity in CD8 + TILs exhaustion and suggests its possible regulatory mechanism, which is feasible in clinical evaluation and beneficial for novel immunotherapeutic approaches in DLBCL.
论文信息
- 作者
- Yang Y、Shu Y、Qin Z、Zeng Y、Chen K、Liu X、Jian S、Zhu Q
- 第一作者单位
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan road, Nanchong, Sichuan, 637000, China.China
- 通讯作者单位
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan road, Nanchong, Sichuan, 637000, China. 359059927@qq.com.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Biology direct2025 Aug 13
- 原文标识
- PubMed 40804681 · DOI 10.1186/s13062-025-00684-1
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