Immune microenvironment modulation following neoadjuvant therapy for oesophageal adenocarcinoma: a translational analysis of the DEBIOC clinical trial

IF 7.1 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2024-10-11 DOI:10.1016/j.esmoop.2024.103930

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引用次数: 0

Abstract

Background

The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant oxaliplatin and capecitabine (Xelox) ± AZD8931 in oesophageal adenocarcinoma (OAC) but limited efficacy. We evaluated the impact of neoadjuvant Xelox ± AZD8931, a novel small-molecule inhibitor with equipotent activity against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2 and HER3, on biological pathways using a unique software-driven solution.

Patients and methods

Transcriptomic profiles from 25 pre-treatment formalin-fixed paraffin-embedded OAC biopsies and 18 matched resection specimens, treated with Xelox + AZD8931 (n = 16) and Xelox alone (n = 9), were analysed using the Almac clara^T total mRNA report analysing 92 gene signatures, 100 unique single-gene drug targets and 7337 single genes across 10 hallmarks of cancer. Gene-set enrichment analysis (GSEA) was utilised to investigate pathways governing pathological response. Tumour-infiltrating lymphocytes (TILs) were assessed digitally using the QuPath software.

Results

Hierarchical clustering identified three molecular subgroups classified by activation of innate immune signalling. The immune-high subgroup was associated with HER2 positivity, increased pathological response and a marked reduction in immune signalling and TILs following neoadjuvant therapy. The immune-low cluster was predominantly HER2/EGFR-negative, and EGFR positivity was associated with the immune-mixed subgroup. Treatment with neoadjuvant therapy induced common resistance mechanisms, such as angiogenesis and epithelial–mesenchymal transition signalling, and a reduction in DNA repair signatures. Addition of AZD8931 was associated with reduction of expression of EGFR, HER2 and AKT pathways and also promoted an immunosuppressive microenvironment. GSEA showed that patients with a pathological response to treatment had increased immune signalling, whereas non-responders to neoadjuvant therapy were enriched for nucleotide repair and cellular growth through the action of E2F transcription factors.

Conclusion

OAC may be subdivided into three immune-related subgroups which undergo modulation in response to neoadjuvant therapy with marked suppression of the immune microenvironment in HER2-positive/immune-high tumours.

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食管腺癌新辅助疗法后的免疫微环境调节：DEBIOC 临床试验的转化分析

背景据食管胃癌（DEBIOC）双重Erb B抑制试验报告，新辅助奥沙利铂和卡培他滨（Xelox）±AZD8931治疗食管腺癌（OAC）的安全性可接受，但疗效有限。我们使用一种独特的软件驱动解决方案评估了新辅助 Xelox ± AZD8931（一种对表皮生长因子受体（EGFR）、人表皮生长因子受体（HER）2 和 HER3 具有同等活性的新型小分子抑制剂）对生物通路的影响。患者和方法使用 Almac claraT 总 mRNA 报告分析了治疗前 25 例福尔马林固定石蜡包埋的 OAC 活检样本和 18 例匹配的切除标本的转录组图谱，这些样本分别接受了 Xelox + AZD8931（n = 16）和 Xelox 单药（n = 9）治疗，分析了 92 个基因特征、100 个独特的单基因药物靶点和 7337 个单个基因，涉及癌症的 10 个特征。基因组富集分析（GSEA）用于研究病理反应的通路。使用 QuPath 软件对肿瘤浸润淋巴细胞（TILs）进行了数字评估。免疫高亚群与 HER2 阳性、病理反应增加以及新辅助治疗后免疫信号和 TIL 明显减少有关。免疫低下亚组主要是HER2/EGFR阴性，EGFR阳性与免疫混合亚组有关。新辅助疗法诱导了常见的耐药机制，如血管生成和上皮-间质转化信号，以及DNA修复特征的减少。AZD8931的加入与表皮生长因子受体、HER2和AKT通路表达的减少有关，同时也促进了免疫抑制微环境的形成。GSEA显示，对治疗有病理反应的患者免疫信号增强，而对新辅助治疗无反应的患者则通过E2F转录因子的作用增强了核苷酸修复和细胞生长。

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

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.