Immunotherapy that improves response to chemotherapy in high-grade serous ovarian cancer

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-11-22 DOI:10.1038/s41467-024-54295-x

Samar Elorbany, Chiara Berlato, Larissa S. Carnevalli, Eleni Maniati, Simon T. Barry, Jun Wang, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill

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Abstract

Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.

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可改善高级别浆液性卵巢癌化疗反应的免疫疗法

对高级别浆液性卵巢癌（HGSOC）网膜活检组织中的肿瘤浸润免疫细胞进行单细胞 RNA 测序（scRNAseq），发现了可增强对新辅助化疗（NACT）反应的潜在靶点。对64,097个细胞的分析发现，NACT诱导巨噬细胞中的稳定素-1（clever-1）和Tregs中的FOXP3过表达，并在蛋白质水平上得到证实。体外抑制 STAB1 可诱导抗肿瘤巨噬细胞。FOXP3 反义寡核苷酸（FOXP3-ASO）能使 Tregs 重新极化为效应 T 细胞表型。对来自 HGSOC 合成小鼠模型的 69,781 个细胞进行的 ScRNA 序列分析再现了患者的数据。在两种 HGSOC 合成小鼠模型中，化疗与抗 Stabilin1 抗体和/或 Foxp3-ASO 的结合能显著提高腹膜疾病小鼠的存活率，在第三种模型中，化疗与抗 Stabilin1 抗体和/或 Foxp3-ASO 的结合能显著提高无进展存活率。长期存活者（300 天以上）对肿瘤再侵袭具有抵抗力。抗stabilin1抗体使肿瘤中富含CXCL9+巨噬细胞，Foxp3-ASO增加了TBET细胞浸润。我们的研究结果表明，靶向免疫细胞中的这些分子可改善患者的化疗反应。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.