弥漫性大B细胞淋巴瘤
癌症研究
生物
淋巴瘤
免疫系统
CD8型
T细胞
免疫学
作者
Xiyue Xu,Y Z Zhang,Yaxiao Lu,Xiaoyan Zhang,Cuicui Zhao,Jie-Song Wang,Qingpei Guan,Yingfang Feng,Meng Gao,Jingwei Yu,Zheng Song,Xia Mao Liu,Zahra Golchehre,L. Li,Weihua Ren,Qiang Pan-Hammarström,Huilai Zhang,Linyu Li
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-04-18
标识
DOI:10.1158/0008-5472.can-23-2874
摘要
Abstract Recurrent abnormalities in immune surveillance-related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and natural killer (NK) cells and is recurrently mutated and deleted in DLBCL, suggesting it may play a role in regulating antitumor immunity. Herein, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA-sequencing, whole-exome sequencing, and single-cell RNA-sequencing in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled DLBCL patients. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free and overall survival. Single-cell RNA sequencing revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the Lyn/CD22/SHP1 axis, thereby limiting PD-L1 and IDO expression. Elevated PD-L1 and IDO expression in CD58 deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to CAR T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PD-L1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to CAR T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL.
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