Low CXCL11 expression is indicative of poor prognosis in rectal cancer patients undergoing preoperative chemoradiotherapy: a retrospective cohort study.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.