肿瘤细胞治疗研究
英文原题：CD58 Alterations Govern Antitumor Immune Responses by Inducing PDL1 and IDO in Diffuse Large B-Cell Lymphoma.
在全部入组的DLBCL患者中，CD58突变率为9.1%，拷贝数缺失率为44.7%。
免疫监视相关基因的反复异常影响弥漫性大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NK细胞上的CD2受体相互作用，在DLBCL中反复发生突变和缺失，提示其可能在调节抗肿瘤免疫中发挥作用。在本研究中，我们通过靶向下一代测序、RNA测序（RNA-seq）、全外显子组测序和单细胞RNA-seq，对初诊DLBCL患者的CD58基因组特征进行了全面分析。在所有入组DLBCL患者中，CD58突变率为9.1%，拷贝数缺失率为44.7%。值得注意的是，CD58基因改变以及CD58低表达与R-CHOP治疗应答率降低及较差的PFS和OS显著相关。单细胞RNA-seq显示，肿瘤细胞中CD58表达与CD8+ T细胞耗竭/功能障碍状态呈负相关。由CD58改变导致的T细胞活化不足不能仅归因于CD2信号。CD58通过激活LYN/CD22/SH2结构域含磷酸酶1（SHP1）轴抑制JAK2/STAT1通路活性，从而限制PDL1和IDO表达。CD58缺陷的DLBCL细胞中PDL1和IDO表达升高，导致免疫逃逸和肿瘤内在的CAR-T细胞治疗耐药。直接激活CD58-CD2共刺激信号联合抗PDL1阻断或IDO抑制剂可使CD58缺陷的DLBCL对CAR-T细胞治疗敏感。总之，本研究揭示了CD58在调节DLBCL抗肿瘤免疫应答中的多重作用。意义：CD58缺失通过LYN/CD22/SHP1信号通路上调PDL1和IDO，介导弥漫性大B细胞淋巴瘤的免疫逃逸和治疗耐药，为改善患者治疗提供了潜在靶点和治疗策略。
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 NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq 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 patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq 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/SH2 domain-containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.
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