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Abstract：
BACKGROUND: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis.
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.
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.
摘要：
背景：卵巢癌（OC）仍然是当今女性面临的最具挑战性和致命的恶性肿瘤之一。虽然PARP抑制剂（PARPis）改变了晚期OC女性的治疗前景，许多患者会复发,PARPi耐药是医疗需求未得到满足的领域.靶向PD-1/PD-L1的传统免疫疗法未能在OC中显示任何益处。CD47/TSP-1轴可能与OC相关。我们旨在描述铂类药物治疗后CD47表达的变化及其与免疫特征和预后的关系。
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.
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.
