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

Abstract

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.

The Single Cell Transcriptional Landscape of Esophageal Adenocarcinoma and Its Modulation by Neoadjuvant Chemotherapy

“…CXCL13 plays a key role in the development of tertiary lymphoid structures through engagement with CXCR5 + follicular helper cells and B cell recruitment, although CD8 + CXCL13 + T cells are observed in many tumors and enriched within exhausted PD-1 high subsets (Thommen et al, 2018), (Workel et al, 2019),(van der Leun et al, 2020). CCL4 attracts innate cells and its serum level is increased in EAC where it correlates with both the degree of lymphocytic in ltrate and superior clinical outcome (Donlon et al, 2020). Important modi cations of the T cell repertoire were seen after chemotherapy with a marked reduction in T regulatory populations together with relative enhancement of effector pools.…”

The Prognostic Value of the Lymph Node in Oesophageal Adenocarcinoma; Incorporating Clinicopathological and Immunological Profiling

“…Known functions of bFGF include the enhancement of tumour cell proliferation, survival, motility, and wound healing [40]. Previous studies in oesophageal cancer demonstrated that bFGF overexpression is associated with a risk of tumour recurrence and reduced OS post-surgical resection, suggesting bFGF may play an important role in TME remodelling and enhancement of tumour progression [41,42].…”

The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma

“…It has been reported that when tumor cells overexpressing HMGB1 co-cultured with B cells, the proliferating B cells can be induced to express VEGF and then elevate angiogenesis ( 121 ). A significant decrease in VEGF-C has been found in high tumor lymphocytic infiltration ( 122 ). It is reported that low expression of CD80 can be associated with VEGF overexpression.…”