12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer.
12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer.
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DOI：
10.1002/ijc.32982
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发表时间：
2020-07-15
影响因子：
6.4
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中科院分区：
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三级淋巴样结构（TLS）提供免疫学上的抑制作用。最近的证据将肿瘤组织中独特的12-趋化因子（CCL 2，−3，−4，−5，−8，−18，−19，−21，CXCL 9，−10，−11，−13）签名状态与TLS表达联系起来。然而，12-趋化因子签名状态对于临床使用的潜在意义是未知的。我们的目的是评估结直肠癌（CRC）患者预后与12-趋化因子签名状态的相关性。我们使用了来自法国、日本和美国的三个独立队列（GSE 39582、来自熊本大学医院的KUMAMOTO和TCGA）中切除的975例CRC病例的综合数据。分析了12-趋化因子标记状态与临床病理学特征、患者结局、TLS表达状态和关键肿瘤分子特征的相关性。在发现队列中，具有低12-趋化因子特征状态的患者具有显著较短的无复发生存期（HR：1.61，95%CI：1.11-2.39，p = 0.0123），这在验证队列中得到证实（HR：3.31，95%CI：1.33-10.08，p = 0.0087）。高12-趋化因子签名状态与右侧肿瘤、高肿瘤定位TLS表达、BRAF突变、CIMP高状态和MSI高状态显著相关。此外，基于RNA-seq的分析显示，高12-趋化因子标签状态与炎症相关、免疫细胞相关和凋亡途径（使用基因集富集分析）以及更多的肿瘤浸润免疫细胞（例如细胞毒性T淋巴细胞和骨髓树突状细胞）（使用MCP计数器分析）强烈相关。我们研究了12-趋化因子签名状态在接受切除术的CRC患者中的有希望的作用。我们的数据可能有助于开发新的免疫治疗策略CRC。
Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12-chemokine (CCL2, −3, −4, −5, −8, −18, −19, −21, CXCL9, −10, −11, −13) signature status from tumor tissue and the TLS expression. However, the potential significance of 12-chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12-chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12-chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12-chemokine signature status had a significant shorter relapse-free survival in discovery cohort (HR: 1.61, 95% CI: 1.11–2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33–10.08, p = 0.0087). High 12-chemokine signature status had significant associations with right-sided tumor, high tumor-localized TLS expression, BRAF mutant, CIMP-high status and MSI-high status. Furthermore, RNA-seq based analysis showed that high 12-chemokine signature status was strongly associated with inflammation-related, immune cells-related and apoptosis pathways (using gene set enrichment analysis), and more tumor-infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP-counter analysis). We investigated a promising effect of 12-chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.