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.

中文翻译：

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CD58 改变通过诱导弥漫性大 B 细胞淋巴瘤中的 PD-L1 和 IDO 来控制抗肿瘤免疫反应


免疫监视相关基因的反复异常会影响弥漫性大 B 细胞淋巴瘤 (DLBCL) 的进展并调节对治疗干预的反应。 CD58 与 T 细胞和自然杀伤 (NK) 细胞上的 CD2 受体相互作用，并且在 DLBCL 中反复突变和缺失，表明它可能在调节抗肿瘤免疫中发挥作用。在此，我们通过靶向二代测序、RNA测序、全外显子组测序和单细胞RNA测序，全面分析了初诊DLBCL患者的CD58基因组特征。所有入组的DLBCL患者CD58突变率为9.1%，拷贝数丢失率为44.7%。值得注意的是，CD58 基因改变以及低 CD58 表达与 R-CHOP 治疗反应率降低以及无进展生存期和总生存期较差显着相关。单细胞 RNA 测序显示肿瘤细胞中 CD58 的表达与 CD8+ T 细胞耗竭/功能障碍状态呈负相关。 CD58 改变导致的 T 细胞激活不足不能仅仅归因于 CD2 信号传导。 CD58通过激活Lyn/CD22/SHP1轴来抑制JAK2/STAT1通路的活性，从而限制PD-L1和IDO的表达。 CD58 缺陷的 DLBCL 细胞中 PD-L1 和 IDO 表达升高导致免疫逃避和肿瘤对 CAR T 细胞治疗的内在耐药性。 CD58-CD2 共刺激信号的直接激活与抗 PD-L1 阻断或 IDO 抑制剂相结合，使 CD58 缺陷的 DLBCL 对 CAR T 细胞疗法敏感。总的来说，这项工作确定了 CD58 在调节 DLBCL 抗肿瘤免疫反应中的多重作用。