CD58 alterations govern antitumor immune responses by inducing PD-L1 and IDO in diffuse large B-cell lymphoma
Cancer Res. 2024 Apr 18. doi: 10.1158/0008-5472.CAN-23-2874. Online ahead of print.ABSTRACTRecurrent 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 resistanc...
Source: Cell Research - Category: Cytology Authors: Xiyue Xu Yidan Zhang Yaxiao Lu Xiaoyan Zhang Cuicui Zhao Jiesong Wang Qingpei Guan Yingfang Feng Meng Gao Jingwei Yu Zheng Song Xia Liu Zahra Golchehre Lanfang Li Weicheng Ren Qiang Pan-Hammarstr öm Huilai Zhang Xianhuo Wang Source Type: research