Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependant apoptotic cell death and chemotherapy is thought to further promote tumor apoptosis1. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival2,3. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics4,5. Here we report that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo RIP3 deletion or RIP1 inhibition was protective against oncogenic progression and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment (TME) associated with intact RIP1/RIP3 signaling was in-part contingent on necroptosis-induced CXCL1 expression whereas CXCL1 blockade was protective against PDA. Moreover, we found that cytoplasmic SAP130 was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle – its cognate receptor – was upregulated in tumor-infiltrating myeloid cells. Mincle ligation by SAP130 promoted oncogenesis whereas Mincle deletion was protective and phenocopied the immunogenic reprogramming of the TME characteristic of RIP3 deletion. Cellular depletion experiments suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects in the context of RIP3 or Mincle deletion. As such, T cells which are dispensable to PDA progression in hosts with intact RIP3 or Mincle signaling become reprogrammed into indispensable mediators of anti-tumor immunity in absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signaling which critically promote macrophage-induced adaptive immune suppression enabling PDA progression.

Clonal deletion and functional inactivation of self-reactive cells have been invoked as mechanisms underlying intrathymic development of T-cell tolerance. The relative importance of these mechanisms in the development of tolerance of more mature, peripheral T cells either to self or to exogenous antigens is unclear, although recent data relate the development of T-cell tolerance in the periphery to clonal anergy. We have now investigated the induction of extrathymic tolerance using BALB/c mice that were made tolerant to Staphylococcus aureus enterotoxin B, a superantigen which specifically interacts in such mice with T cells bearing V beta 8 antigen receptors. Both euthymic and athymic mice made tolerant to S. aureus enterotoxin B had a markedly reduced number of V beta 8.1,2+ CD4+ peripheral T cells. This reduction was accompanied by genomic DNA fragmentation that is associated with cell death. These results indicate that a deletional mechanism can contribute to the induction of T-cell tolerance in peripheral lymphoid cells.

MyD88 blockade exaggerates the ability of dendritic cells to promote the transition from chronic pancreatitis to pancreatic cancer.