title: The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.
abstract: Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. 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. 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.
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Seifert
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Werba
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Nancy Ngoc
authors.initials: NN
authors.lastname: Giao Ly
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Alothman
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Dalia
authors.initials: D
authors.lastname: Alqunaibit
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Avanzi
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Rocky
authors.initials: R
authors.lastname: Barilla
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Donnele
authors.initials: D
authors.lastname: Daley
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Greco
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Torres-Hernandez
authors.affiliation: Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pergamo
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Zambirinis
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Mridul
authors.initials: M
authors.lastname: Pansari
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rendon
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tippens
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Mautin
authors.initials: M
authors.lastname: Hundeyin
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Vishnu R
authors.initials: VR
authors.lastname: Mani
authors.affiliation: Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hajdu
authors.affiliation: Cold Spring Harbor Laboratories, Cold Spring Harbor, New York 11724, USA.
authors.forename: Dannielle
authors.initials: D
authors.lastname: Engle
authors.affiliation: S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.|Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D000093542:Gemcitabine
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C113583:Clecsf8 protein, mouse; C475895:Cxcl1 protein, mouse; D020690:GTPase-Activating Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; C490620:Ralbp1 protein, mouse; D003841:Deoxycytidine; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D000093542:Gemcitabine