CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor.
Expression of CD200, the gene encoding the ligand for the inhibitory immune receptor CD200R, is an independent prognostic factor for various forms of leukemia predicting worse overall survival of the patients. The enhanced expression of CD200 on the tumors implies that anti-tumor responses can be enhanced by blockage of the CD200-CD200R interaction. Indeed, antibody-mediated blockade of the CD200-CD200R inhibitory axis is currently evaluated in clinical tests to boost immune responses against CD200-expressing tumors. Here, we show that mice lacking CD200, the exclusive ligand for CD200R, are resistant to chemical skin carcinogenesis. Importantly, CD200R controls tumor outgrowth independently of CD200 expression by the tumor cells themselves. Furthermore, Cd200(-/-) mice do not become tolerant to intranasally administered antigens, suggesting that tumor rejection is normally suppressed through CD200-induced immune tolerance. Decreased tumor outgrowth is accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6 by the lymph node (LN) dendritic cells. During carcinogenesis, skin-draining LNs of Cd200(-/-) mice contain increased numbers of IL-17-producing FoxP3(+) cells, which preferentially home to the tumors. Thus, the CD200-CD200R axis induces tolerance to external and tumor antigens and influences the T-regulatory/Th17 cell ratio. We demonstrate for the first time that the absence of CD200R signaling inhibits outgrowth of an endogenous tumor irrespective of CD200 expression by the tumor cells. This important paradigm shift leads to a much broader applicability of CD200-blockade in the treatment of tumors.
Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
T P
TP
Rygiel
G
G
Karnam
G
G
Goverse
A P J
AP
van der Marel
M J
MJ
Greuter
R A
RA
van Schaarenburg
W F
WF
Visser
A B
AB
Brenkman
R
R
Molenaar
R M
RM
Hoek
R E
RE
Mebius
L
L
Meyaard
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D007108:Immune Tolerance; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010212:Papilloma / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology*
D015703:Antigens, CD; C492346:CD200 receptor, mouse; D002273:Carcinogens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008562:Membrane Glycoproteins; C042739:antigens, CD200