Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-07-31 DOI:10.1016/j.ccell.2025.07.005

Eleonora Ghisoni, Fabrizio Benedetti, Aspram Minasyan, Mathieu Desbuisson, Paula Cunnea, Alizée J. Grimm, Noémie Fahr, Charlotte Capt, Nicolas Rayroux, Flavia De Carlo, Doga C. Gulhan, Julien Dagher, David Barras, Matteo Morotti, Juan A. Marín-Jiménez, Bovannak Stewen Chap, Tania Santoro, Giulia Spagnol, Mapi Fleury, Katerina Fortis, Denarda Dangaj Laniti

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Abstract

Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors. We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression. We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent Brca1^mut tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE₂ signaling. Conversely, recurrent Brca1^wt tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring Trem2/ApoE^high tumor associated macrophages (TAMs) and Nduf4l2^high/Galectin3^high malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers. Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.

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髓系细胞网络控制复发性卵巢癌原始免疫景观的重建

免疫疗法在复发性卵巢癌（OC）中显示出有限的成功，其预后见解主要来自于未经治疗的肿瘤。我们分析了来自5个独立队列的595名OC患者的697个肿瘤样本（566个原发和131个复发），捕获肿瘤浸润淋巴细胞（TIL）异质性，并确定了与预后和TIL相关的四种免疫表型：髓系网络驱动恶性进展。我们发现，在临床前小鼠模型中，与发炎的人类OCs类似，复发的Brca1mut肿瘤维持激活的TILs：树突状细胞（dc）壁龛，但通过上调COX/PGE2信号传导逃避免疫控制。相反，复发的Brca1wt肿瘤表现出TILs:DCs小生境的缺失和积累的免疫抑制肿瘤微环境（TME）网络，其特征是Trem2/ApoEhigh的肿瘤相关巨噬细胞（tam）和Nduf4l2high/ galectin - 3高的恶性状态。复发性肿瘤再现了原发肿瘤的免疫原性特征。我们的研究结果揭示了brca依赖性TIL：髓系串音是复发性OC持续免疫原性的关键，并提出了提高化疗疗效的新靶点。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.