Altered T Cell Migratory Capacity in the Progression from Barrett Oesophagus to Oesophageal Adenocarcinoma

Abstract

Oesophageal adenocarcinoma (OAC) is an inflammation-driven cancer with poor prognosis and incidence is increasing rapidly. OAC arises from gastro-oesophageal reflux disease (GORD) and reflux-induced Barrett oesophagus (BO). The role of T cells in this disease progression is not yet fully understood. We have previously demonstrated higher proportions of pro-tumour Th2 cells in BO tissue, implicating them in its pathogenesis. While a Th2 immune profile is thought to underlie the metaplastic transformation in BO and promote OAC development, our studies suggest that the abundance of Th2 cells in BO tissue is likely to occur through altered T cell recruitment. This study examined the chemokine networks governing T cell migration to oesophageal tissue during disease progression. Here, we have identified that circulating T cells in OAC patients, exhibit impaired migratory capacity with decreased frequencies of Th1-associated CXCR3 + and Th17-associated CCR6 + cells. Despite the abundance of Th1 chemokines RANTES (CCL5) and MIP-1α (CCL3) in OAC tumour, enrichments of intratumoural T cells expressing corresponding receptors were not observed. These data suggest that T cell infiltration of oesophageal tissue is compromised in OAC and suggest that future therapies targeting T cell trafficking should occur at the pre-neoplastic stage. This is supported by the finding that antagonism of Th2-biased CCR4 significantly reduces T cell migration in BO but not OAC patients. Since we have previously reported a predominant Th2 immune profile in BO, we suggest that chemokine receptor antagonism may be a viable treatment option to alleviate Th2-predominance in BO and interrupt progression to OAC.

Fractalkine Elicits Chemotactic, Phenotypic, and Functional Effects on CX3CR1+CD27− NK Cells in Obesity-Associated Cancer

“…Furthermore, NK cell migration toward chemotactic cues in EAC omentum, but not tumor, can be significantly reduced by antagonizing the fractalkine receptor CX3CR1. Importantly, this approach could be used to increase the availability of NK cells for migration toward alternative chemotactic signals in EAC tumor (27). In addition, we have identified that fractalkine induces a conversion from CX3CR1 1 CD27 À to a CX3CR1 À CD27 1 phenotype in NK cells, which is representative of the dominant NK cell phenotype in EAC omentum and is well established as the less cytolytic and predominantly cytokine-producing population (2830).…”

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

“…Despite the immunoregulatory, a potential tumor-promoting action ascribed to such effector T cells, the presence of elevated systemic CCL22 may also indicate uninhibited function of antigen presenting cells, which are important for orchestrating anti-tumor responses and therefore result in a net positive effect when elevated in the periphery. Indeed, previous work by our colleagues has demonstrated that CCL22 expression in EAC tumors is relatively low compared to EAC serum [ 36 ]. Much less is known about the role of CCL26 in cancer, however elevated levels of this chemokine in tumors have been reported in later stage colorectal cancer and has been associated with worse prognosis [ 37 ].…”

FLOT and CROSS Chemotherapy Regimens Alter The Frequency of CD27+ and CD69+ T Cells in Oesophagogastric Adenocarcinomas; Implications for Combination with Immunotherapy.

“…Biopsies were enzymatically digested to perform OGJ cell phenotyping, as previously published [16]. Brie y, tissue was minced using a scalpel and digested in collagenase solution (2 mg/ml of collagenase type IV (Sigma) in Hanks Balanced Saline Solution (GE healthcare) supplemented with 4% (v/v) foetal bovine serum) at 37°C and 1500 rpm on an orbital shaker.…”