Lipid and neutrophil accumulation and active inflammasome in high BMI tumor regions of human pancreatic ductal adenocarcinoma.

Abstract

e16271 Background: Obesity is an established risk factor for cancer and cancer-related mortality. Adipocytes may act as a “damage” signal resulting in the accumulation of innate immune cells, fueling an inflammatory micro-environment. Among the innate immune cells, tumor-associated neutrophils (TANs) are confirmed to accumulate inside the tumor. As obesity is a significant risk factor for a poorer prognosis in pancreatic ductal adenocarcinoma (PDAC), we hypothesize that obesity-driven adipose fuels the progression of PDAC in a TAN and inflammasome-facilitated manner. This may happen through several mechanisms, including genomic instability of aggressive PDAC clonal populations. Methods: Tissue from resected tumors of PDAC patients (n = 44) with a body-mass index (BMI) > 27 (obese [n = 21]) and BMI < 22 (normal [n = 23]) were incubated with anti-human CD66b antibodies and detected using standard immunofluorescent microscopy techniques. Images were acquired in a Zeiss Axioplan microscope workstation and analyzed by ZEN and Metamorph software. Results: We identified the presence of adipocytes in all tissue sections and CD66b+ neutrophils in all tissue sections of normal BMI patients and in 81% of high BMI patients. There is a significantly greater density of adipocytes in the tumor environment when compared to adjacent normal areas, suggesting that these cells are acting as a damage signal. We have also shown that there are fewer total cells per area in the tumor region, suggesting a disorganization that may allow more adipose tissue to form in these areas of high BMI patients. Our novel data also shows that high BMI results in a significantly higher neutrophil count in tumor specific tissue when compared to patients with a low BMI. These data suggest an association between BMI and inflammasome accumulation in the tumor environment. Conclusions: Our data uniquely shows that CD66b+ neutrophils tend to accumulate inside PDAC in high BMI patients and this is associated with intra-tumoral active inflammasomes. The higher concentrations of these inflammasomes in higher BMI patients may be of mechanistic relevance in understanding how inflammation induces progression of PDAC. A larger cohort of tissues from PDAC obtained from low and high BMI individuals will be needed to test our hypothesis and to begin to decipher the role of obesity on inflammation and PDAC progression.