Linking Circulating Serum Proteins with Clinical Outcomes in Esophageal Adenocarcinoma—An Emerging Role for Chemokines

Abstract

Simple SummaryCancer of the esophagus (food pipe) is an aggressive type of cancer with poor prognosis and rates are increasing. Current treatments help to prolong survival but only for a minority of patients, therefore there is an urgent need to discover why some people do not respond and to develop new and improved treatments. Newer treatments targeting the immune system show promise but the anti-tumor immune response in esophageal cancer is not well understood. This study measured levels of 54 immune markers in serum of patients with esophageal cancer and evaluated a link with patient clinical outcomes, e.g., survival time, response to treatment, and adverse events. We found that certain chemokines, proteins which control immune cell trafficking, were particularly high in patients who survived longer (CCL22 and CCL26) and responded to treatment (CCL4), suggesting the importance of immune cell movement in orchestrating an effective immune response to esophageal cancer.Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.