title: Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth.
abstract: Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immunosurveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape is still incomplete. Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T-cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T-cell immunity and suppress tumor growth.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: Luping
authors.initials: L
authors.lastname: Lin
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
authors.forename: Anshu
authors.initials: A
authors.lastname: Malhotra
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Dikov
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D051881:Receptor, Notch1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A