The CD47/TSP-1 axis: a promising avenue for ovarian cancer treatment and biomarker research.

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-08-14 DOI:10.1186/s12943-024-02073-0
Aurélie Moniot, Christophe Schneider, Laure Chardin, Elisa Yaniz-Galende, Catherine Genestie, Marion Etiennot, Aubéri Henry, Coralie Drelon, Audrey Le Formal, Benoit Langlois, Laurence Venat, Christophe Louvet, Laure Favier, Alain Lortholary, Dominique Berton-Rigaud, Nadine Dohollou, Christophe Desauw, Michel Fabbro, Emmanuelle Malaurie, Coraline Dubot, Jean Emmanuel Kurtz, Nathalie Bonichon Lamichhane, Éric Pujade-Lauraine, Albin Jeanne, Alexandra Leary, Stéphane Dedieu
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引用次数: 0

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.

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CD47/TSP-1 轴:卵巢癌治疗和生物标志物研究的前景广阔的途径。
背景: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。尽管PARP抑制剂(PARPis)改变了晚期卵巢癌女性患者的治疗格局,但许多患者仍会复发,PARP耐药患者的医疗需求仍未得到满足。以 PD-1/PD-L1 为靶点的传统免疫疗法未能在 OC 中显示出任何疗效。CD47/TSP-1 轴可能与 OC 相关。我们旨在描述CD47表达在铂治疗中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试验中收集的OC患者的肿瘤和血液样本进行CD47和TSP-1评估,并使用多重分析法研究免疫标记物。考虑到靶向 CD47/TSP-1 轴的治疗意义,我们在侵袭性卵巢癌的临床前模型中使用了 CD47 衍生的 TAX2 肽来选择性地拮抗它:结果:NACT后观察到CD47表达明显减少。基线CD47表达最高的肿瘤患者在NACT后CD4+和CD8+T细胞流入量最大,预后较好。此外,TSP-1 的血浆水平在 NACT 后显著下降,TSP-1 高与预后较差有关。我们证明,TAX2 在小鼠体内具有选择性和良好的生物分布特征,可在肿瘤部位定位。我们利用显示 PARPi 耐药性的相关腹膜癌模型,证明了在奥拉帕利(PARPi)后给药 TAX2 能显著减轻肿瘤负担并延长生存期。值得注意的是,即使在奥拉帕利疗效允许的治疗条件下,连续使用 TAX2 也能提高动物的存活率: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疗法中获益;(2)表明 TAX2 是 PARP 抑制剂复发患者的潜在替代疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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