卵巢癌（OC）仍然是当今女性面临的最具挑战性和致命性的恶性肿瘤之一。虽然 PARP 抑制剂 (PARPis) 改变了晚期 OC 女性的治疗格局，但许多患者会复发，而 PARPi 耐药环境是一个未得到满足的医疗需求领域。针对 PD-1/PD-L1 的传统免疫疗法未能在 OC 中显示出任何益处。 CD47/TSP-1 轴可能与 OC 相关。我们的目的是描述铂类治疗后 CD47 表达的变化及其与免疫特征和预后的关系。在新辅助化疗 (NACT) 和多重化疗之前和之后，对 CHIVA 试验中从 OC 患者收集的肿瘤和血液样本进行 CD47 和 TSP-1 评估分析用于研究免疫标记。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。NACT 后观察到 CD47 表达显着降低。基线时具有最高 CD47 表达谱的肿瘤患者在 NACT 后表现出最大的 CD4 和 CD8 T 细胞流入，并表现出更好的预后。此外，NACT 下 TSP-1 血浆水平显着下降，高 TSP-1 与较差的预后相关。我们证明 TAX2 在小鼠中表现出选择性且有利的生物分布特征，定位于肿瘤部位。使用显示 PARPi 耐药性的相关腹膜癌病模型，我们证明奥拉帕尼后（PARPi 后）施用 TAX2 可显着降低肿瘤负荷并延长生存期。值得注意的是，即使在允许奥拉帕尼疗效的治疗条件下，顺序使用 TAX2 也能够提高动物存活率。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治疗中受益，并且 (2) 表明TAX2 是 PARP 抑制剂复发患者的潜在替代疗法。© 2024。作者。

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.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.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.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.© 2024. The Author(s).