PO.ET06.06 · 实验与分子治疗
EBV LMP1与MYD88 L265P突变对PD-1抑制剂在ABC-DLBCL中疗效的协同机制的初步探索
Preliminary exploration of the synergistic mechanism between EBV LMP1 and MYD88 L265P mutation on the efficacy of PD-1 Inhibitors in ABC-DLBCL
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摘要 Abstract
中文摘要
背景：活化B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL）侵袭性强，预后差。Epstein-Barr病毒（EBV）感染和MYD88 L265P突变是ABC-DLBCL中的关键分子驱动因素，通常表现为相互排斥，可能是由于功能重叠。PD-1抑制剂在未经筛选的复发/难治性DLBCL患者中疗效有限。然而，我们对复发/难治性非GCB DLBCL患者的回顾性分析提示，罕见的“双阳性”（EBV阳性/MYD88 L265P突变）患者对PD-1抑制剂具有更高的反应率。
目的：本研究探讨了EBV LMP1如何在MYD88 L265P突变（导致组成性JAK/STAT活化）的背景下调节细胞内信号传导，并评估了其与PD-1抑制剂替雷利珠单抗的协同效应。
方法：分析了54例接受PD-1抗体治疗的复发/难治性非GCB DLBCL患者的临床数据。患者按EBER原位杂交（EBV）和MYD88测序进行分层。使用HBL-1细胞系（MYD88 L265P突变，EBV阴性）。通过转染过表达LMP1。分组：对照、单用替雷利珠单抗、LMP1过表达、LMP1+替雷利珠单抗。qPCR检测NF-κB p65、MMP9、c-Myc、TLR3、STAT3、JAK3、LMP1、PD-1、PD-L1的mRNA水平。Western blot检测关键分子的蛋白表达和磷酸化。
结果：在21例具有完整分子数据的患者中，两例“双阳性”患者均获得客观缓解（100%），而EBV阴性/MYD88突变组（n=9）为22.2%，EBV阳性/MYD88野生型组（n=5）为60.0%。HBL-1细胞显示高基线p-JAK3和p-STAT3。LMP1过表达抑制了p-JAK3和p-STAT3。HBL-1细胞表达肿瘤细胞内在的PD-1 mRNA。单用替雷利珠单抗抑制了p-JAK3/p-STAT3磷酸化。LMP1过表达与替雷利珠单抗联合显示出最强的抑制作用，表明存在协同效应。
结论：MYD88 L265P突变可能导致肿瘤细胞对由肿瘤细胞内在PD-1信号维持的STAT3活化产生成瘾。LMP1的共存增加了抑制压力，可能增强这种依赖性。替雷利珠单抗阻断可能产生合成致死效应。联合EBV状态和MYD88分析可预测DLBCL中PD-1抑制剂的敏感性，尚需进一步验证。
查看英文原文 English abstract
Background: Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is aggressive with poor prognosis. Epstein-Barr virus (EBV) infection and the MYD88 L265P mutation are key molecular drivers in ABC-DLBCL, typically exhibiting mutual exclusivity, potentially due to functional overlap. PD-1 inhibitors show limited efficacy in unselected relapsed/refractory DLBCL patients. However, our retrospective analysis of relapsed/refractory non-GCB DLBCL patients suggested that rare "double-positive" (EBV-positive/MYD88 L265P mutant) patients had higher response rates to PD-1 inhibitors.
Objective: This study investigated how EBV LMP1 modulates intracellular signaling in the context of MYD88 L265P mutation (causing constitutive JAK/STAT activation) and evaluated its synergistic effect with the PD-1 inhibitor tislelizumab.
Methods: Clinical data from 54 relapsed/refractory non-GCB DLBCL patients treated with PD-1 antibodies were analyzed. Patients were stratified by EBER ISH (EBV) and MYD88 sequencing. The HBL-1 cell line (MYD88 L265P mutant, EBV-negative) was used. LMP1 was overexpressed via transfection. Groups: control, tislelizumab alone, LMP1 overexpression, LMP1+tislelizumab. qPCR measured mRNA levels of NF-κB p65, MMP9, c-Myc, TLR3, STAT3, JAK3, LMP1, PD-1, PD-L1. Western blot detected protein expression and phosphorylation of key molecules.
Results: Among 21 patients with complete molecular data, both "double-positive" patients achieved an objective response (100%), compared to 22.2% in EBV-negative/MYD88 mutant (n=9) and 60.0% in EBV-positive/MYD88 wild-type (n=5) groups. HBL-1 cells showed high baseline p-JAK3 and p-STAT3. LMP1 overexpression suppressed p-JAK3 and p-STAT3. HBL-1 cells expressed tumor cell-intrinsic PD-1 mRNA. Tislelizumab alone inhibited p-JAK3/p-STAT3 phosphorylation. The combination of LMP1 overexpression and tislelizumab showed the strongest inhibition, indicating synergy.
Conclusion: MYD88 L265P mutation may cause tumor cell addiction to STAT3 activation maintained by tumor cell-intrinsic PD-1 signaling. LMP1 co-existence adds inhibitory pressure, potentially enhancing this dependency. Tislelizumab blockade may yield a synthetic lethal effect. Combined EBV status and MYD88 profiling could predict PD-1 inhibitor sensitivity in DLBCL, requiring further validation.
利益披露 Disclosure
C. Wang, None..
Y. Lin, None..
J. Wang, None.