A multi-omics analysis of advanced triple-negative breast cancer identifies predictors to chemo-immunotherapy and on-treatment dynamics.

IF 14 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2026-10-20 Epub Date: 2026-09-29 DOI:10.1016/j.xcrm.2026.103080

Nicolaas Van Renne, Elisa Agostinetto, Andrea Joaquín García, Marie Morfouace, Marcin Możejko, Zoë Denis, Sophie Déglise, Bernd Bodenmiller, Henoch S Hong, David Venet, Marcela Carausu, Robin Liechti, Stéphanie Tissot, Sylvie Rusakiewicz, Mattia Rediti, Xavier Catteau, Daniel Schulz, Delphine Loirat, Daniel Herrero Saboya, Philippe Aftimos, Matteo Benelli, Angel L Guerrero-Zotano, Andrea Gombos, Hans Wildiers, Jip Van Dinter, Ariane Sickinghe, Nicolas Penel, Jean-Charles Goeminne, Júlio Oliveira, Birute Brasiuniene, Emanuela Romano, Justin M Balko, Marleen Kok, Ewa Szczurek, Christos Sotiriou, Laurence Buisseret

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引用次数: 0

Abstract

No validated biomarkers beyond PD-L1 currently guide immune checkpoint inhibition (ICI) in advanced triple-negative breast cancer (TNBC), and how tumors remodel their microenvironment in response to ICI remains incompletely understood. We perform a temporal analysis of patients with advanced TNBC treated with chemo-immunotherapy in the SYNERGY trial (NCT03616886; n = 84) and the EORTC-1553-SPECTA initiative (NCT02834884; n = 38) using RNA sequencing, whole-exome sequencing, multiplex immunofluorescence, and imaging mass cytometry. A transcriptomic progression-free survival (PFS)-based risk signature stratifies outcomes and is validated across ICI-treated cohorts, while showing context-dependent behavior in non-ICI settings. Favorable outcomes are associated with immune-enriched tumors with organized lymphoid architecture, while poor outcomes are linked to fibrotic, angiogenic microenvironments with frequent PI3K alterations. Upon treatment, early progression was characterized by fibrovascular remodeling, macrophage expansion, and upregulation of alternative immunosuppressive mediators. These findings establish fibrovascular and myeloid reprogramming as a coordinated resistance program, identify actionable therapeutic targets, and support microenvironment stratification in future ICI-based trials.

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晚期三阴性乳腺癌的多组学分析确定了化疗免疫治疗和治疗动态的预测因素。

目前在晚期三阴性乳腺癌（TNBC）中，除了PD-L1之外，还没有经过验证的生物标志物指导免疫检查点抑制（ICI），并且肿瘤如何重塑其微环境以响应ICI仍然不完全清楚。我们对SYNERGY试验（NCT03616886, n = 84）和EORTC-1553-SPECTA计划（NCT02834884, n = 38）中接受化疗免疫治疗的晚期TNBC患者进行了时间分析，方法包括RNA测序、全外显子组测序、多重免疫荧光和成像细胞术。基于转录组无进展生存（PFS）的风险特征对结果进行分层，并在ici治疗的队列中进行验证，同时在非ici环境中显示情境依赖性行为。良好的结果与免疫富集的肿瘤有组织的淋巴样结构有关，而不良的结果与纤维化、血管生成微环境频繁发生PI3K改变有关。治疗后，早期进展表现为纤维血管重构、巨噬细胞扩张和替代免疫抑制介质上调。这些发现建立了纤维血管和髓细胞重编程作为一个协调的耐药程序，确定了可行的治疗靶点，并支持未来基于ci的试验中的微环境分层。

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

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.