Spatially Resolved Transcriptomics Deconvolutes Histological Prognostic Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases-猫眼课题宝

DOI：

10.1101/2022.09.21.508569

发表时间：

2022-09

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

C. Wood;K. Pennel;H. Leslie;A. Legrini;Andrew J Cameron;Lydia Melissourgou-Syka;J. Quinn;H. V. van Wyk;Jennifer Hay;A. Roseweir;C. Nixon;C. Roxburgh;D. McMillan;A. Biankin;O. Sansom;P. Horgan;J. Edwards;C. Steele;N. Jamieson

背景：对原发性结直肠癌（CRC）表现出强烈免疫应答的患者在手术后具有生存益处，而那些以基质微环境为主的患者则表现不佳。用于识别结直肠癌肝转移（CRLM）患者的生物标志物在寡转移性疾病手术后具有良好的预后仍然难以捉摸。本研究的目的是确定一个简单的免疫细胞浸润和间质含量的组织学评估在预测原发性CRC和CRLM同步切除后的结果中的实际应用，并询问驱动疾病进展的潜在功能生物学。方法对原发性CRC和CRLM同时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。进行与基因组特征的整合、途径富集分析和免疫去卷积。结果高免疫转移与提高肿瘤特异性生存率相关（HR，0.36，P=0.01）。大量转录组学分析被基质含量混淆，但ST证明长期存活者转移的侵袭性边缘的特征在于富集II型干扰素信号传导（内斯=-2.05 P.Adj<0.005）和MHC-II类抗原呈递（内斯=-2.09 P.Adj<0.005）的适应性免疫细胞群。相比之下，预后不良的患者表现出调节性T细胞和中性粒细胞丰度增加，在转移性肿瘤中心富集Notch（内斯=2.2 P.Adj=0.022）和TGF-β（内斯=2.2 P.Adj=0.02）信号传导途径。结论组织学评估对CRLM同步切除患者的结局进行了分层。ST分析揭示了显著的肿瘤内和病变间异质性，其中在驱动每种表型中鉴定了潜在的转录组学程序。翻译相关性目前的研究表明，准确的免疫细胞浸润和间质含量的组织学评估可以确定切除少转移性肝病（与原发性结直肠癌同时出现）后患者的生存期。空间转录组学方法已经证明了患者之间、同一患者的匹配病变之间以及单个病变内的异质性。在浸润性边缘具有高免疫浸润的患者在长期存活者中表现出淋巴细胞浸润和相关的适应性免疫途径上调。在肿瘤边缘具有低免疫浸润的标本中，观察到存活率显著降低，这是通过上调的免疫抑制途径和转移灶周围先天免疫细胞的优势确定的。空间转录组学可用于检查CRC转移进展的驱动因素，并识别具有反应性和抑制性免疫微环境的患者。在更大的队列中的应用将建立CRLM的制图，而在未来，研究可能会评估该技术在治疗前和治疗后活检样本中的应用，目的是预测个体治疗反应。目前的研究强调了批量和ST衍生数据之间的差异，同时证明了去卷积转录组确定免疫谱的准确性。现在ST策略在规模上变得更加可实现，这对原发性和转移性CRC的批量转录组签名的解释具有影响。

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. TRANSLATIONAL RELEVANCE The current study demonstrates that accurate histological assessment of immune cell infiltration and stromal content can define survival in patients following resection of oligometastatic liver disease when presenting synchronously with primary colorectal cancer. A spatial transcriptomic approach has demonstrated heterogeneity between patients, between matched lesions in the same patient and within individual lesions. Patients with high immune infiltrates at the invasive margin demonstrated lymphocytic infiltration and associated upregulated adaptive immune pathways in long term survivors. In specimens with low immune infiltrate at the tumor edge a significant reduction in survival was observed, this was determined by upregulated immunosuppressive pathways and a predominance of innate immune cells surrounding metastases. Spatial transcriptomics can be used to examine drivers of metastatic progression in CRC and identifies patients with reactive and suppressed immune microenvironments. Application across a larger cohort will build the cartography of CRLM, while in future, studies may assess application of this technology to pre and post treatment biopsy samples with the aim of predicting individual therapeutic responses. The current study has highlighted discrepancies between bulk and ST derived data whilst demonstrating accuracy of deconvoluted transcriptome to determine immune profiling. Now that ST strategies are becoming more achievable at scale, this has implications for the interpretation of the bulk transcriptomic signatures both of primary and metastatic CRC.

Spatially Resolved Transcriptomics Deconvolutes Histological Prognostic Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases

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