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 (CX3CR1^INT) are defined as peripheral memory, those expressing the highest levels (CX3CR1^HI) are effector memory/terminally differentiated and those lacking CX3CR1 (CX3CR1^NEG) 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 CX3CR1^INT and CX3CR1^HI 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 CX3CR1^NEG CD8⁺ T cells express higher levels of L-selectin than CX3CR1^INT CD8⁺ T cells. This is consistent with previous reports and implicates fractalkine in the conversion of CX3CR1^INT CD8⁺ T cells to a CX3CR1^NEG 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 CX3CR1^NEG CD8⁺ T cell populations.

Keywords: CX3CR1; T cells; adhesion; fractalkine; inflammation; obesity; omentum; upper gastrointestinal cancer.