title: Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy.
abstract: Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNγ and/or TNFα into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8(+) effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFα stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFα substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFα promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.
authors.affiliation: Western Australian Institute for Medical Research, University of Western Australia,  Centre for Medical Research, Laboratory for Cancer Medicine, Perth 6000,  Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Johansson
authors.forename: Juliana
authors.initials: J
authors.lastname: Hamzah
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Payne
authors.forename: Ruth
authors.initials: R
authors.lastname: Ganss
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000276:immunology*; D055099:Neuroendocrine Cells / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma