Background: Patients demonstrating strong immune responses to primary colorectal cancer (CRC) have a survival benefit following surgery, while those with predominantly stromal microenvironments do poorly. Biomarkers to identify patients with colorectal cancer liver metastases (CRLM) who have good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary CRC and CRLM, and to interrogate the underlying functional biology that drives disease progression. Methods: Patients undergoing synchronous resection of primary CRC and CRLM underwent detailed histological assessment, panel genomic and bulk transcriptomic assessment, immunohistochemistry (IHC) and GeoMx Spatial Transcriptomics (ST) analysis. Integration with genomic features, pathway enrichment analysis and immune deconvolution were performed. Results: High-immune metastases were associated with improved cancer specific survival (HR, 0.36, P=0.01). Bulk transcriptomic analysis was confounded by stromal content but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for Type II Interferon signalling (NES=-2.05, P.Adj<0.005) and MHC Class II Antigen Presentation (NES=-2.09 P.Adj<0.005). In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T-cells and neutrophils with enrichment of Notch (NES=2.2 P.Adj=0.022) and TGF β (NES=2.2 P.Adj=0.02) signalling pathways at the metastatic tumor centre. Conclusions: Histological assessment stratifies outcome in patients undergoing synchronous resection of CRLM. ST analysis reveals significant intra-tumoral and inter lesional heterogeneity with underlying transcriptomic programmes identified in driving each phenotype.

中文翻译：

---

空间分辨的转录组学解卷积结直肠癌和同步肝转移患者的组织学预后亚组

背景：对原发性结直肠癌 (CRC) 表现出强烈免疫反应的患者在手术后有生存获益，而以基质微环境为主的患者则表现不佳。用于识别结肠直肠癌肝转移 (CRLM) 患者在寡转移性疾病手术后预后良好的生物标志物仍然难以捉摸。本研究的目的是确定免疫细胞浸润和基质含量的简单组织学评估在预测原发性 CRC 和 CRLM 同步切除后结果的实际应用，并探究驱动疾病进展的潜在功能生物学。方法：对原发性 CRC 和 CRLM 同步切除的患者进行详细的组织学评估、面板基因组和批量转录组评估，免疫组织化学 (IHC) 和 GeoMx 空间转录组学 (ST) 分析。进行了与基因组特征、通路富集分析和免疫反卷积的整合。结果：高免疫转移与提高癌症特异性生存率相关（HR，0.36，P=0.01）。大量转录组分析被基质含量混淆，但 ST 证明长期幸存者转移灶的侵袭性边缘以富集 II 型干扰素信号 (NES=-2.05, P.Adj<0.005) 和 MHC 的适应性免疫细胞群为特征II 类抗原呈递 (NES=-2.09 P.Adj<0.005)。相反，预后不良的患者表现出调节性 T 细胞和中性粒细胞的丰度增加，同时 Notch (NES=2.2 P.Adj=0.022) 和 TGF β (NES=2.2 P.Adj=0. 02) 转移性肿瘤中心的信号通路。结论：组织学评估对接受同步切除 CRLM 的患者的结果进行分层。ST 分析揭示了显着的肿瘤内和病灶间异质性，以及在驱动每种表型时确定的潜在转录组程序。