Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo.
CD70 (CD27 ligand) promotes the expansion of primed lymphocytes by enhancing cell survival. Surprisingly, we previously observed that CD70 aberrantly expressed on human glioma cells promoted immune cell apoptosis and inhibited alloreactive lysis. Here we report that ectopic expression of CD70 in mouse glioma cells enhances apoptosis of T, B and NK cells in coculture, but nevertheless promotes glioma cell lysis by NK cells in vitro. In nude mice, CD70 expression in SMA-560 gliomas delays the glioma growth upon subcutaneous (s.c.) or intracerebral (i.c.) inoculation, suggesting a role for CD70/CD27-dependent NK cell activity in tumor surveillance. In syngeneic immunocompetent VM/Dk mice, CD70 allows the rejection of s.c. and i.c. implanted SMA-560 tumors. The tumorigenicity of CD70-expressing glioma cells is abrogated when TGF-beta signaling is blocked. Moreover, mice surviving the s.c. CD70 glioma challenge subsequently also reject wild-type glioma cells administered i.c. Similarly, CD70-expressing GL-261 gliomas are rejected in syngeneic C57BL/6 mice, while glioma growth is restored in C57BL/6 CD27(-/-) mice, suggesting that the CD70/CD27 interaction recruits a tumor-specific T-cell repertoire and induces tumor-specific memory. Altogether, these observations indicate that the net effect of aberrant CD70 expression in gliomas is immune stimulatory rather than immune paralytic and encourage its application in tumor immunotherapy.
Aulwurm
Steffen
S
Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, School of Medicine, University of Tübingen, Tübingen, Germany. steffen.aulwurm@uni-tuebingen.de
Wischhusen
Jörg
J
Friese
Manuel
M
Borst
Jannie
J
Weller
Michael
M
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D017209:Apoptosis; D001402:B-Lymphocytes; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D053282:CD27 Ligand; D005910:Glioma / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013601:T-Lymphocytes / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000276:immunology*
D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; C505772:Cd70 protein, mouse; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; D048069:Tumor Necrosis Factors