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.

中文翻译：

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12-趋化因子特征，结直肠癌肿瘤复发的预测因子。

三级淋巴结构 (TLS) 提供免疫抗肿瘤作用。最近的证据表明来自肿瘤组织和TLS 表达式。然而，12-趋化因子特征状态对临床使用的潜在意义尚不清楚。我们旨在评估 12 种趋化因子特征状态与结直肠癌 (CRC) 患者预后的关系。我们使用了来自法国、日本和美国的三个独立队列（GSE39582、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 趋化因子特征状态与临床病理学特征、患者结果、TLS 表达状态和关键肿瘤分子特征的关联。发现队列中 12 种趋化因子特征状态低的患者无复发生存期显着缩短（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 趋化因子特征状态与右侧肿瘤、高肿瘤局部 TLS 表达、BRAF 突变体、CIMP 高状态和 MSI 高状态显着相关。此外，基于 RNA-seq 的分析表明，高 12 趋化因子特征状态与炎症相关、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（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）。我们研究了 12 趋化因子特征状态对接受切除的 CRC 患者的有希望的影响。我们的数据可能有助于开发新的 CRC 免疫治疗策略。