Yang Yiming, Shu Yaqi, Qin Zujun, Zeng Yi, Chen Kexin, Liu Xin, Jian Shunhai, Zhu Qiqi
Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan road, Nanchong, Sichuan, 637000, China.
Department of Pathology, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China.
Biol Direct. 2025 Aug 13;20(1):92. doi: 10.1186/s13062-025-00684-1.
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 CD8TILs and its underlying regulatory mechanism in DLBCL.
The metabolic alterations in exhausted CD8TILs in DLBCL were evaluated through single-cell RNA sequencing (scRNA-seq). The crucial metabolic pathway and its significance in the biological function of exhausted CD8TILs 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 CD8TILs exhaustion was explored through scRNA-seq, RNA sequencing, and somatic mutation analysis.
Our study illustrated the metabolic heterogeneity in CD8TILs, and demonstrated that oxidative phosphorylation (OXPHOS) was the crucial pathway in CD8TILs exhaustion. The high OXPHOS activity indicated the immune deficiency in exhausted CD8TILs, 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 CD8TILs.
Our study highlights the importance of OXPHOS activity in CD8TILs exhaustion and suggests its possible regulatory mechanism, which is feasible in clinical evaluation and beneficial for novel immunotherapeutic approaches in DLBCL.
代谢改变与CD8肿瘤浸润淋巴细胞（TILs）的耗竭和免疫缺陷密切相关，而关于弥漫性大B细胞淋巴瘤（DLBCL）的相关情况却知之甚少。本研究旨在阐明DLBCL中耗竭的CD8 TILs代谢改变的意义及其潜在调控机制。
通过单细胞RNA测序（scRNA-seq）评估DLBCL中耗竭的CD8 TILs的代谢改变。利用scRNA-seq和RNA测序研究关键代谢途径及其在耗竭的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评估关键代谢途径中的标记基因，以及其与耗竭状态、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索与CD8 TILs耗竭相关的代谢改变所涉及的潜在调控机制。
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耗竭的关键途径。高OXPHOS活性表明耗竭的CD8 TILs存在免疫缺陷，UQCRFS1被鉴定为标记基因。高UQCRFS1表明免疫抑制性TME、严重的临床病理特征，包括活化B细胞样亚型、高国际预后指数（IPI）和体能状态（PS）评分、晚期、预后不良以及对ICB治疗耐药。此外，DLBCL中的MYC相关信号传导和P2RY8突变可能调节耗竭的CD8 TILs中UQCRFS1的表达。
我们的研究强调了OXPHOS活性在CD8 TILs耗竭中的重要性，并提出了其可能的调控机制，这在临床评估中是可行的，且有利于DLBCL的新型免疫治疗方法。
