CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity‐associated cancer

Abstract

Obesity is a global health problem presenting serious risk of disease fuelled by chronic inflammation, including type 2 diabetes mellitus, cardiovascular disease, liver disease and cancer. Visceral fat, in particular the omentum and liver of obese individuals are sites of excessive inflammation. We propose that chemokine-mediated trafficking of pro-inflammatory cells to the omentum and liver contributes to local and subsequent systemic inflammation. Oesophagogastric adenocarcinoma (OAC) is an exemplar model of obesity and inflammation driven cancer. We have demonstrated that T cells actively migrate to the secreted factors from the omentum and liver of OAC patients and that both CD4 + and CD8 + T cells bearing the chemokine receptor CCR5 are significantly more prevalent in these tissues compared to matched blood. The CCR5 ligand and inflammatory chemokine MIP-1α is also secreted at significantly higher concentrations in the omentum and liver of our OAC patient cohort compared to matched serum. Furthermore, we report that MIP-1α receptor antagonism can significantly reduce T cell migration to the secreted factors from OAC omentum and liver. These novel data suggest that chemokine receptor antagonism may have therapeutic potential to reduce inflammatory T cell infiltration to the omentum and liver and in doing so, may ameliorate pathological inflammation in obesity and obesity-associated cancer.

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

“…Such frequencies were still significantly lower than CD8 + T cell frequencies in non-cancer controls suggesting that the fractalkine:CX3CR1 axis might be perturbed by malignancy in this study cohort. Together with our previously reported data, our investigations suggest that fractalkine together with MIP-1α in the omentum recruit inflammatory T cells to this tissue in EAC, most likely contributing to the pathological adipose tissue inflammation at the expense of effective anti-tumor immunity ( 19 ). As other studies have shown that fractalkine serves distinctive roles in different inflammatory diseases such as diabetes, dermatitis, asthma, and neuropathic pain, we propose that it may also serve functions additional to T cell chemotaxis in the omentum of EAC patients ( 8 , 11 , 12 , 28 ).…”

“…We have previously shown that the omentum is a hot bed of T cell-mediated inflammation in patients with esophagogastric adenocarcinoma (EAC), a malignancy that arises in a background of inflammation and importantly has one of the strongest associations with obesity of all malignancies ( 18 ). Furthermore, we have identified the macrophage inflammatory protein-1alpha (MIP-1α)/CCR1 axis as a key pathway governing T cell migration to the omentum of EAC patients and reported its therapeutic potential in the space of obesity-associated inflammation ( 19 ). 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 ).…”

Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells <i>in vivo</i>

“…CCX9588 has been previously reported to decrease chemotaxis of T-cells towards liver conditioned media in vitro. 46 CCX9588 is an analogue of CCX354, which has previously been investigated as a therapeutic for rheumatoid arthritis in a clinical trial, 47 and CCX721, which has been shown to have anti-osteolytic activity in an in vivo MM model. 23 Together with previous studies demonstrating that targeting of CCR1 prevents the development of severe osteolytic lesions in vivo, and our data demonstrating that CCR1 is an independent prognostic factor in MM patients, our study suggests that CCR1 is a potential attractive therapeutic target for MM.…”

Regulation, Communication, and Functional Roles of Adipose Tissue-Resident CD4+ T Cells in the Control of Metabolic Homeostasis

“…Another CCR5 ligand, CCL3, is also secreted at significantly high levels in the omentum of patients with an obesity and inflammation-driven cancer oesophagogastric adenocarcinoma (OAC). Antagonizing CCL3 receptor, including CCR5 and CCR1, significantly reduces T cell migration to the omentum of OAC patients ( 92 ). As obesity develops, human adipocytes release the chemokine CCL20 and promote T cell migration into VAT via its receptor CCR6 ( 61 ).…”