Parallel Profiles of Inflammatory and Effector Memory T Cells in Visceral Fat and Liver of Obesity-Associated Cancer Patients

Abstract

In the midst of a worsening obesity epidemic, the incidence of obesity-associated morbidities, including cancer, diabetes, cardiac and liver disease is increasing. Insights into mechanisms underlying pathological obesity-associated inflammation are lacking. Both the omentum, the principal component of visceral fat, and liver of obese individuals are sites of excessive inflammation, but to date the T cell profiles of both compartments have not been assessed or compared in a patient cohort with obesity-associated disease. We have previously identified that omentum is enriched with inflammatory cytokines, chemokines and T cells. Here, we compared the inflammatory profile of T cells in the omentum and liver of patients with the obesity-associated malignancy oesophageal adenocarcinoma (OAC). Furthermore, we assessed the secreted cytokine profile in OAC patient serum, omentum and liver to assess systemic and local inflammation. We observed parallel T cell cytokine profiles and phenotypes in the omentum and liver of OAC patients, in particular CD69(+) and inflammatory effector memory T cells. This study reflects similar processes of inflammation and T cell activation in the omentum and liver, and may suggest common targets to modulate pathological inflammation at these sites.

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

“…Fractalkine-driven migration of T cells to omentum in EAC is likely to contribute to the CD8 + T cell-mediated adipose tissue inflammation previously demonstrated in these patients ( 22 , 23 ). In pilot data not shown, we have also found lower levels of soluble fractalkine in tumor compared to omentum in our patient cohort.…”

“…Known inducers of fractalkine include the inflammatory cytokines IFN-γ, TNF-α, and IL-1β ( 13 ). Such an abundance of fractalkine was unsurprising as we have reported enrichments of IFN-γ and TNF-α producing T cells together with secreted IL-1β in the omentum of EAC patients ( 13 , 22 , 23 ). Interestingly, significantly higher fractalkine levels were observed in the patients with highest serum CRP levels, which is indicative of its role in meta-inflammation and in line with previous reports of the circulating levels of CRP and fractalkine in metabolic dysfunction ( 7 , 27 ).…”

“…Peripheral blood mononuclear cells (PBMC) were isolated by density centrifugation using Ficoll-Paque™ Plus (GE Healthcare, Uppsala, Sweden). Omental samples (10 g from each patient) were digested enzymatically to obtain SVF as previously described ( 22 , 23 ). Adipose tissue conditioned media (ACM) was prepared as previously described ( 22 ).…”

“…However, the fractalkine pathway may present a more attractive and more specific therapeutic target in this setting as there is only one known receptor for this chemokine (CX3CR1), in contrast to the redundancy observed in other chemokine pathways ( 1 , 20 , 21 ). We have already demonstrated that the omentum of EAC patients is primed for fractalkine-mediated inflammation through an abundance of TNF-α-producing CD8 + and CD4 + T cells and secreted IL-1β and here, we address the role of fractalkine in inflammatory and cytotoxic T cell trafficking and retention in this inflamed tissue ( 22 , 23 ). These questions are extremely relevant at a time when the global obesity problem has reached epidemic proportions and shows no signs of abating ( ).…”

Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists

“…Interestingly, it could be shown that activated T RM cells were increased in the visceral fat and liver tissue of these patients, indicating a systemic immune activation. The activated T RM cells in the liver and adipose tissue produced pro-inflammatory cytokines, such as IL-1β, IL-12, GM-CSF, IL-6, IL-2, IL-4 and IL-15 [ 96 ]. These findings indicate that T RM cells could contribute to the overall pro-inflammatory phenotype in obese patients, which is one of the reasons for chronic inflammatory diseases like NAFLD and cancer development ( Figure 4 ).…”