Summary Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts but their functional contribution remains unknown. Transgenic mice with ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either non-invasive precursor (PanIN) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition and cancer stem cells, with diminished animal survival. In PDAC patients, lower myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblasts depleted mouse tumors. While myofibroblasts depleted tumors did not respond to Gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.

The influence of the microenvironment on tumour progression is becoming clearer. In this Review we address the role of an essential signalling pathway, that of transforming growth factor-β, in the regulation of components of the tumour microenvironment and how this contributes to tumour progression.

Professional antigen presenting cells, dendritic cells (DC) are responsible for initiation and maintenance of immune responses. Here, we report that a substantial proportion of DCs in tumor-bearing mice and cancer patients have increased levels of triglycerides. Lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to up-regulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of MHC and co-stimulatory molecules. However, lipid-laden DCs had reduced capacity to process antigens. Pharmacological normalization of lipid levels in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of a cancer vaccine. These findings support the regulation of immune responses in cancer by manipulation of lipid levels in DCs.

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype.

IntroductionThe endogenous adenine nucleotides and adenosine are normally present at low concentrations in the extracellular milieu. However, metabolically stressful conditions, including inflammation and hypoxia characteristic of asthma, solid tumors, and other pathologic conditions, result in dramatic increases in extracellular concentrations of adenosine. [1][2][3] There are also mechanisms of nonlytic secretion of adenosine during hypoxic conditions.There is growing evidence that adenosine can actively modulate differentiation and function of myeloid cells. 4 Circulating cells of myeloid lineage, including monocytes and dendritic cell (DC) precursors, migrate to tissues where they differentiate into macrophages or DCs. DCs show impressive interaction with the adjacent microenvironment, 5,6 which regulates formation of DC subtypes and their functional properties, including expression of cytokines and growth factors. Because of rapid growth, solid tumors routinely experience severe hypoxia and necrosis, which causes adenine nucleotide degradation and adenosine release. Therefore, high levels of extracellular adenosine contribute to the local tumor microenvironment and may greatly influence differentiation of DCs from monocyte/macrophages and DC precursors migrating into tumor tissue. Adenosine acts through 4 subtypes of adenosine receptors, A 1 , A 2A , A 2B , and A 3 , which are members of the G-protein-coupled family of receptors. 7,8 A 2A adenosine receptors are generally anti-inflammatory, whereas A 2B and A 3 receptors are implicated in proinflammatory action of adenosine. Adenosine receptors are expressed abundantly on monocytes, and through these receptors adenosine exerts substantial modulatory effects on monocyte function and further differentiation. A 1 receptors were shown to stimulate formation of giant multinucleated cells from monocytes, whereas A 2 receptors inhibited this process. 9 A 2B receptors were implicated in mediating the inhibitory effect of adenosine on macrophage proliferation induced by M-CSF. 10 Exogenous adenosine can prevent monocytes from differentiating into macrophages, leading them to an intermediate differentiation stage between immature DCs and monocytes. 11 Cyclic nucleotides, including cAMP, which intracellular level increases in response to stimulation of adenosine A 2 receptors, regulate certain steps of monocyte differentiation and promote their differentiation toward a CD1a low CD14 ϩ/low CD209 ϩ intermediate cell but impair differentiation into functional DCs. 12 Up-regulation of DC-specific ICAM-3-grabbing nonintegrin (CD209) was not affected by cyclic nucleotides, 12 indicating that DC development was not blocked at the monocyte stage. The expression of all 4 adenosine receptor subtypes has been reported in human monocytes and myeloid DCs. 9,13-15 However, the effects of adenosine on differentiation of myeloid DCs from monocytes, macrophages, and hematopoietic progenitor cells (HPCs) and the roles of specific adenosine receptor subtypes involved in this process hav...