CCL4 and MIF: Prognostic Biomarkers for Evaluating the Chemoradiotherapy Response and Prognosis in Patients with ESCC

Background: Radiotherapy plays a central role in therapeutic strategy of local-advanced oesophageal squamous cell carcinoma. The aim of this study was to investigate cytokine profiles in serum of patients with ESCC and evaluate the potential utility of cytokine markers in predicting CRT response and prognostic prediction. Methods: CCL4, MIF and CXCL8 in the serum samples who were participating in a phase II clinical trial (NCT02959385) were determined. The association between these cytokines and CRT response as well as prognostic prediction were subsequently assessed in ESCC. Subsequently, the results were verified in ESCC tissue and in the Cancer Genome Atals (TCGA) database. Results: The expression of 120 cytokines were evaluated in serum of 4 ESCC patients with excellent CRT-response and 4 patients with CRT-resistance by cytokine microarrays. CCL3, CCL4, MIF, PLAUR and CXCL8 were screened. CCL4, MIF and CXCL8 were further detected by ELISA in other 60 patients enrolled in this study. Upregulation of CCL4, CXCL8 and MIF were observed in patients with excellent CRT-response. Elevated expression of CCL4 and MIF were closely associated with improved PFS and OS outcomes. Similar results were obtained in other 46 ESCC tumor tissues. 82 ESCC patients in TCGA database with increased CCL4 and MIF expression exhibited the favorable immunocyte infiltration and enriched immune response-related pathways, which indicates the preferable tumor immunogenicity. Conclusions: CCL4 and MIF are identified as dependable and prognostic biomarkers for evaluating the response to CRT and prognosis in patients with ESCC.