TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis.
Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.
Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, 72076 Tübingen, Germany.
Nele
N
Müller-Hermelink
Heidi
H
Braumüller
Bernd
B
Pichler
Thomas
T
Wieder
Reinhard
R
Mailhammer
Katrin
K
Schaak
Kamran
K
Ghoreschi
Amir
A
Yazdi
Roland
R
Haubner
Christian A
CA
Sander
Ralph
R
Mocikat
Markus
M
Schwaiger
Irmgard
I
Förster
Ralph
R
Huss
Wolfgang A
WA
Weber
Manfred
M
Kneilling
Martin
M
Röcken
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods; D007340:Insulinoma / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014916:Whole-Body Irradiation
D000957:Antigens, Viral, Tumor; D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D039302:Integrin alphaVbeta3; C490620:Ralbp1 protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D007371:Interferon-gamma