Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n = 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, α-smooth muscle actin (α-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF)] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n = 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target.

Worldwide, the aging population, globalization, rapid urbanization, and population growth have fundamentally changed disease patterns. Noncommunicable diseases (NCDs), of which cardiovascular disease (CVD) accounts for nearly half, have overtaken communicable diseases as the world’s major disease burden. CVD remains the No. 1 global cause of death, accounting for 17.3 million deaths per year, a number that is expected to grow to 23.6 million by 2030. Increasingly, the populations affected are those in low- and middle-income countries, where 80% of these deaths occur, usually at younger ages than in higher-income countries, and where the human and financial resources to address them are most limited (1). The epidemiological transition occurring is exacerbated by the lack of vital investment in sustainable health policies to address and curtail the risk factors associated with CVD and NCDs. Recognizing the profound mismatch between the need for investment in the prevention and control of CVD at the global and national level and the actual resources allocated, the international CVD community, under the umbrella of the World Heart Federation, joined the NCD community to call for a United Nations (UN) High-level Meeting on Noncommunicable Diseases, held in September 2011. At this meeting, heads of state signed a Political Declaration that committed governments to the development of 4 specific measures to address the NCD burden in a specific timeline: 1) Recommendations for a global monitoring framework that included NCD targets to be completed by the end of 2012; 2) development of a plan for an effective multisector partnership by the end of 2012; 3) national NCD plans by 2013; and 4) a comprehensive review to evaluate progress, to take place in 2014

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.