Construction of the Prediction Model for Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiotherapy Based on Pretreatment Tumor-Infiltrating Macrophage-Associated Biomarkers

Abstract

Purpose To assess the value of macrophage-related biomarkers (CD163, CD68, MCSF, and CCL2) for predicting the response to neo-chemoradiotherapy (NCRT) and the prognosis of locally advanced rectal cancer (LARC). Methods We enrolled 191 patients who underwent neoadjuvant chemoradiotherapy and radical resection between 2011 and 2015. Tumor tissues were collected before NCRT with a colonoscope and post-surgery and were subjected to immunohistochemical analysis. Results The expression levels of macrophage-related biomarkers (CD163, CD68, MCSF, and CCL2) were lower in the pathological complete response (pCR) group when compared with the non-pCR group (all P<0.05). Based on X-tile plots, we divided the tumors in two groups and found that lower pre-NCRT/post-surgical CD163, CD68, MCSF, CCL2 scores correlated with improved DFS. Cox regression analysis demonstrated that pre-NCRT CD163 (HR=1.008, 95% CI 1.003–1.013, P =0.003) and MCSF (HR=2.187, 95% CI 1.343–3.564, P =0.002) scores were independent predictors of DFS. Based on Cox multivariate analysis, we constructed a risk score model with a powerful ability to predict pCR in LARC patients. Moreover, COX regression analysis was performed to explore the role of the risk score in LARC patients. The results demonstrated that tumor size (HR=1.291, P =0.041), worse pathological TNM stage (HR=1.789, P =0.005, and higher risk score (HR=1.084, P <0.001) were significantly associated with impaired disease-free survival. Based on the above results, a nomogram and decision curve analysis were generated. Conclusion The expression levels of macrophage-related biomarkers CD163, CD68, MCSF, and CCL2 were associated with chemoradiotherapy resistance and prognosis in LARC patients following NCRT. A risk score model was constructed which could be used to predict LARC outcome.

Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review

“…Nevertheless, a study by Kitagawa et al on pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT showed that low CD68+ macrophage counts were more frequently recorded in tumors that poorly responded to CRT [87]. Similar findings were reported by Liu et al in a series of 191 rectal cancer patients treated with preoperative CRT [88] (Table 1). As tumor-associated macrophages (TAMs) can be polarized towards M1-effector or M2-immunosuppressive phenotype, their role in response to RT and prognosis may be differentially driven by the TAM-subtype prevalence [89].…”

Radiomics in the Setting of Neoadjuvant Radiotherapy: A New Approach for Tailored Treatment

“…Adequately predicting the response to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer represents a key factor in order to achieve a fully personalized treatment approach, especially in the case of locally advanced disease presentation, which constitute a well-established indication for radiation therapy [127]. The identification of biomarkers able to predict patients' outcomes (i.e., response to nCRT) currently represents a priority in the radiotherapy research landscape, and imaging-derived response predictors are a topic of active investigation [128][129][130][131][132][133].…”

Tissue-Based Markers as a Tool to Assess Response to Neoadjuvant Radiotherapy in Rectal Cancer—Systematic Review

“…It appears that TAMs affect the tumor microenvironment by suppressing cytotoxic T lymphocyte responses [ 99 ]. In a study of 191 patients with LARC, macrophage-associated biomarkers CD163, CD68, macrophage colony-stimulating factor (MCSF) and C-C chemokine ligand 2 (CCL2) in pre-nCRT and post-surgery tumor tissue were found to be higher in patients who were associated with a poorer response to nCRT and lower in patients with a complete pathological response [ 100 ]. A study of 85 patients revealed that CD26 overexpression in rectal cancer cells was correlated with a poor pathological response to CRT.…”