The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression

• Published in: Nature (London) Vol. 532; no. 7598; pp. 245 - 249
• Main Authors: Seifert, Lena, Werba, Gregor, Tiwari, Shaun, Giao Ly, Nancy Ngoc, Alothman, Sara, Alqunaibit, Dalia, Avanzi, Antonina, Barilla, Rocky, Daley, Donnele, Greco, Stephanie H., Torres-Hernandez, Alejandro, Pergamo, Matthew, Ochi, Atsuo, Zambirinis, Constantinos P., Pansari, Mridul, Rendon, Mauricio, Tippens, Daniel, Hundeyin, Mautin, Mani, Vishnu R., Hajdu, Cristina, Engle, Dannielle, Miller, George
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2016; Nature Publishing Group
• Subjects: 631/67/1504/1713; 631/67/580; 692/699/67/1504/1713; Adenocarcinoma - immunology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Analysis; Animals; Apoptosis; Apoptosis - drug effects; Cancer; Carcinogenesis; Carcinogenesis - drug effects; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemokine CXCL1 - antagonists & inhibitors; Chemokine CXCL1 - metabolism; Chemokines; Chemotherapy; Dendritic cells; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Development and progression; Disease Progression; Female; Gemcitabine; Gene Expression Regulation, Neoplastic; Genetic aspects; GTPase-Activating Proteins - metabolism; Humanities and Social Sciences; Humans; Immune Tolerance; Lectins, C-Type - immunology; Lectins, C-Type - metabolism; letter; Lymphocytes; Male; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Necrosis; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Science; Signal Transduction; Tumors; Up-Regulation; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17403

A study of pancreatic ductal adenocarcinoma shows that cancer cell proliferation is associated with increased expression of proteins that control programmed necrotic cell death and suppress the adaptive immune system. Cell proliferation in pancreatic ductal adenocarcinoma George Miller and colleagues have investigated the role of programmed necrosis in pancreatic ductal adenocarcinoma (PDA). They observe upregulation of the necrosome factors CXCL1 and Mincle, and this correlates with proliferation of the cancer cells. Furthermore, necroptosis induces signalling pathways that lead to suppression of the adaptive immune system, reinforcing the development of PDA. Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis 1 . Conversely, cancer cells often disrupt apoptosis to survive 2 , 3 . Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs 4 , 5 . Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle—its cognate receptor—was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.