METHODS: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma.
RESULTS: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy.
CONCLUSIONS: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.
方法:在新辅助化疗(NACT)前后,对CHIVA试验中OC患者的肿瘤和血液样本的CD47和TSP-1进行评估,并使用多重分析来研究免疫标志物。考虑到靶向CD47/TSP-1轴的治疗相关性,我们使用CD47衍生的TAX2肽在侵袭性卵巢癌的临床前模型中选择性拮抗它.
结果:在NACT后观察到CD47表达的显著降低。在基线时具有最高CD47表达谱的肿瘤患者在NACT后显示出最大的CD4+和CD8+T细胞流入,并且显示出更好的预后。此外,TSP-1血浆水平在NACT下显著下降,高TSP-1与不良预后相关。我们证明了TAX2在小鼠中表现出选择性和有利的生物分布特征,定位在肿瘤部位。使用显示PARPi耐药性的相关腹膜癌模型,我们证明,奥拉帕利(PARPi后)给药TAX2显著降低了肿瘤负荷并延长了生存期.值得注意的是,依次使用的TAX2甚至在允许奥拉帕尼功效的治疗条件下也能够增加动物存活率。
结论:因此,我们的研究(1)提出了基于CD47的患者分层,这些患者最有可能从术后免疫疗法中受益。(2)提示TAX2是PARP抑制剂复发患者的潜在替代疗法.