◥Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell-derived proinflammatory cytokine IL1b is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1b promoted the activation and secretory phenotype of quiescent pancreatic stellate cells and established an immunosuppressive milieu mediated by M2 macrophages, myeloid-derived suppressor cells, CD1d hi CD5 þ regulatory B cells, and Th17 cells. Loss of tumor cell-derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8 þ cytotoxic T cells, attenuated growth of pancreatic neoplasia, and conferred survival advantage to PDA-bearing mice. Accordingly, antibody-mediated neutralization of IL1b significantly enhanced the antitumor activity of a-PD-1 and was accompanied by increased tumor infiltration of CD8 þ T cells. Tumor cell expression of IL1b in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell-derived IL1b in orchestrating an immune-modulatory program that supports pancreatic tumorigenesis.Significance: These findings identify a new modality for immune evasion in PDA that depends on IL1b production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.

Oncogenic activation of Ras is associated with the acquisition of a unique set of metabolic dependencies that contribute to tumor cell fitness. Mutant Ras cells are endowed with the capability to internalize and degrade extracellular protein via a fluid-phase uptake mechanism termed macropinocytosis 1 . There is a growing appreciation for the role of this Ras-dependent process in the generation of free amino acids that can be used to support tumor cell growth under nutrient limiting conditions 2 . However, little is known about the molecular steps that mediate the induction of macropinocytosis by oncogenic Ras. Here we identify vacuolar ATPase (v-ATPase) as an essential regulator of Ras-induced macropinocytosis. Oncogenic Ras promotes the translocation of v-ATPase from intracellular membranes to the plasma membrane (PM) via a pathway that requires protein kinase A (PKA) activation by a bicarbonate-dependent soluble adenylate cyclase (sAC). PM accumulation of v-ATPase is necessary for the cholesterol-dependent association of Rac1 with the PM, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. These observations identify a link between v-ATPase trafficking and nutrient supply by macropinocytosis that could be exploited to curtail the metabolic adaptation capacity of mutant Ras tumor cells.To identify essential mediators of Ras-driven macropinocytosis, we conducted a full genome siRNA screen using a microscopy-based high-throughput assay in which oncogenic HRas (HRasV12)-dependent induction of macropinocytosis in HeLa cells is measured by uptake Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms

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Gain-of-function p53 R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy Graphical abstract Highlights d Gain-of-function Trp53 R172H promotes neutrophil recruitment to pancreatic tumors d Neutrophils in Kras G12D/+ ;Trp53 R172H/+ tumors are due to tumor-cell-derived chemokines d Neutrophils confer resistance to CD40 combination immunotherapy and chemotherapy

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