Identifying a Novel Role for Fractalkine (CX3CL1) in Memory CD8+ T Cell Accumulation in the Omentum of Obesity-Associated Cancer Patients

Abstract

The omentum is enriched with pro-inflammatory effector memory CD8+ T cells in patients with the obesity-associated malignancy, esophagogastric adenocarcinoma (EAC) and we have identified the chemokine macrophage inflammatory protein-1alpha as a key player in their active migration to this inflamed tissue. More recently, others have established that subsets of memory CD8+ T cells can be classified based on their surface expression of CX3CR1; the specific receptor for the inflammatory chemokine fractalkine. CD8+ T cells expressing intermediate levels (CX3CR1INT) are defined as peripheral memory, those expressing the highest levels (CX3CR1HI) are effector memory/terminally differentiated and those lacking CX3CR1 (CX3CR1NEG) are classified as central memory. To date, the fractalkine:CX3CR1 axis has not been examined in the context of CD8+ T cell enrichment in the omentum and here we examine this chemokines involvement in the accumulation of memory CD8+ T cells in the omentum of EAC patients. Our data show that fractalkine is significantly enriched in the omentum of EAC patients and drives migration of T cells derived from EAC patient blood. Furthermore, CX3CR1 is endocytosed specifically by CD8+ T cells upon encountering fractalkine, which is consistent with the significantly diminished frequencies of CX3CR1INT and CX3CR1HI CD8+ T cells in the fractalkine-rich environment of omentum in EAC, relative to matched blood. Fractalkine-mediated endocytosis of CX3CR1 by CD8+ T cells is sustained and is followed by enhanced surface expression of L-selectin (CD62L). These novel data align with our findings that circulating CX3CR1NEG CD8+ T cells express higher levels of L-selectin than CX3CR1INT CD8+ T cells. This is consistent with previous reports and implicates fractalkine in the conversion of CX3CR1INT CD8+ T cells to a CX3CR1NEG phenotype characterized by alterations in the migratory capacity of these T cells. For the first time, these findings identify fractalkine as a driver of T cell migration to the omentum in EAC and indicate that CD8+ T cells undergo sequenced fractalkine-mediated alterations in CX3CR1 and L-selectin expression. These data implicate fractalkine as more than a chemotactic cytokine in obesity-associated meta-inflammation and reveal a role for this chemokine in the maintenance of the CX3CR1NEG CD8+ T cell populations.

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

“…*p ≤ 0.05 responding T cells in this study are also likely due to the redundancy in the chemokine system. Furthermore, it is well reported that many chemokine receptors are internalised upon ligand binding [9,27]. Studies have shown that high levels of chemokines lead to lower levels of their receptors [30,31].…”

“…Studies have shown that high levels of chemokines lead to lower levels of their receptors [30,31]. This complex process is influenced by the signals in the external microenvironment and the differentiation status of the cell [9]. These dynamic processes were not assessed within the scope of this observational study as the principal aim was to assess the expression pattern of chemokines and their receptors in blood and tissue of these patient cohorts.…”

“…In addition, CD4 + T-cells infiltrating tumour tissue displayed a decreased activation profile, compared with normal tissue. While our group have reported the key role of specific chemokine networks in inflammatory T cell migration to the liver and adipose tissue in OAC patients [7][8][9], the chemokine profiles active in the oesophagitis-metaplasia-carcinoma sequence have not been studied in detail. Furthermore, the pathways governing Th2 cell accumulation in oesophageal tissues in BO and a Th1:Th2 mixed profile in OAC are yet to be elucidated.…”

IP3-Mediated Calcium Signaling Is Involved in the Mechanism of Fractalkine-Induced Hyperalgesia Response

“…Fractalkine is widely distributed throughout the spinal cord and brain tissue [10]. A pivotal role of activation by fractalkine in inflammation during central nervous system diseases has been well described by previous studies [11,12].…”

Immune structures of the greater omentum and their role in cancer metastasis

“…Подробно описан механизм этого процесса у больных опухолями пищевода и желудка, связанными с ожирением [45]. Основную роль в их миграции из крови в сальник играет фракталкин -хемокин, вырабатывающийся многими клетками, в том числе адипоцитами [46].…”