Chou Chia-Lin, Lin Cheng-Yi, Li Wan-Shan, Lee Sung-Wei, Yang Ching-Chieh, Tian Yu-Feng, Shiue Yow-Ling, Tsai Hsin-Hwa, Lai Hong-Yue
Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan.
Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan.
Virchows Arch. 2025 Apr;486(4):803-815. doi: 10.1007/s00428-024-03974-7. Epub 2024 Nov 27.
Neoadjuvant concurrent chemoradiotherapy (CCRT) is routinely used before surgery in patients with locally advanced rectal cancer to reduce tumor size and decrease the risk of local recurrence. However, the disease-specific survival has not improved in most cases due to distant metastases. In selected individuals exhibiting a clinical complete response, non-operative management may be allowed; however, those who presented no or little response tend to have an inferior prognosis. Consequently, refined molecular characterization could aid in predicting which patients would benefit from neoadjuvant chemoradiotherapy.
The mRNA level (by transcriptomic profiling) and protein expression (by immunohistochemical staining) of C-X-C motif chemokine ligand 11 (CXCL11) were integrated to predict neoadjuvant chemoradiotherapy efficacy. For survival analysis, clinicopathological features and CXCL11 immunoreactivity that were statistically significant in univariate analysis were included in multivariate analysis using the Cox proportional hazards regression model.
We identified that the CXCL11 level exhibits the most significant downregulation among neoadjuvant chemoradiotherapy non-responders. Using tumor samples from our rectal cancer cohort (n = 343) with immunohistochemistry validation, we demonstrated that low CXCL11 immunoexpression shows significant correlations with advanced disease and positive lymph nodes both prior to and following CCRT (all p < 0.001), vascular and perineural invasion (p < 0.001 and p = 0.006), and poor response to CCRT (p < 0.001). Moreover, low CXCL11 immunoexpression was an independent adverse prognostic factor significantly associated with patient survival. Additionally, we further identified pyroptotic cell death as an unrevealed role of CXCL11 in rectal cancer through bioinformatic analysis.
CXCL11 expression may serve as an early predictor of clinical outcomes and aid in therapeutic decision-making by identifying individuals likely to respond to neoadjuvant chemoradiotherapy in rectal cancer.
新辅助同步放化疗（CCRT）常用于局部晚期直肠癌患者的术前治疗，以缩小肿瘤大小并降低局部复发风险。然而，在大多数情况下，由于远处转移，疾病特异性生存率并未提高。在表现出临床完全缓解的特定个体中，可以允许非手术治疗；然而，那些无反应或反应轻微的患者预后往往较差。因此，精确的分子特征分析有助于预测哪些患者将从新辅助放化疗中获益。
整合C-X-C基序趋化因子配体11（CXCL11）的mRNA水平（通过转录组分析）和蛋白表达（通过免疫组织化学染色）来预测新辅助放化疗疗效。对于生存分析，将单因素分析中具有统计学意义的临床病理特征和CXCL11免疫反应性纳入使用Cox比例风险回归模型的多因素分析。
我们发现CXCL11水平在新辅助放化疗无反应者中表现出最显著的下调。使用我们直肠癌队列（n = 343）的肿瘤样本并经免疫组织化学验证，我们证明低CXCL11免疫表达与CCRT前后的晚期疾病、阳性淋巴结（所有p < 0.001）、血管和神经周围侵犯（p < 0.001和p = 0.006）以及对CCRT的不良反应（p < 0.001）均显著相关。此外，低CXCL11免疫表达是与患者生存显著相关的独立不良预后因素。此外，我们通过生物信息学分析进一步确定细胞焦亡是CXCL11在直肠癌中未被揭示的作用。
CXCL11表达可能作为临床结果的早期预测指标，并通过识别可能对直肠癌新辅助放化疗有反应的个体来辅助治疗决策。
