Role of type 1 IFNs in antiglioma immunosurveillance--using mouse studies to guide examination of novel prognostic markers in humans.
OBJECTIVE
We hypothesized that the type 1 IFNs would play a pivotal role in antiglioma immunosurveillance through promotion of type 1 adaptive immunity and suppression of immunoregulatory cells.


METHODS
We induced de novo gliomas in Ifnar1(-/-) (deficient for type 1 IFN receptors) or wild-type mice by intracerebroventricuar transfection of NRas and a short hairpin RNA against P53 using the Sleeping Beauty transposon system. We analyzed the survival of 587 glioma patients for single nucleotide polymorphisms (SNP) in type 1 IFN-related genes.


RESULTS
Ifnar1(-/-) mice exhibited accelerated tumor growth and death. Analyses of brain tumor-infiltrating lymphocytes in Ifnar1(-/-) mice revealed an increase of cells positive for CD11b(+)Ly6G(+) and CD4(+)FoxP3(+), which represent myeloid-derived suppressor cells and regulatory T cells, respectively, but a decrease of CD8(+) cytotoxic T lymphocytes (CTLs) compared with wild-type mice. Ifnar1(-/-) mouse-derived glioma tissues exhibited a decrease in mRNA for the CTL-attracting chemokine Cxcl10, but an increase of Ccl2 and Ccl22, both of which are known to attract immunoregulatory cell populations. Dendritic cells generated from the bone marrow of Ifnar1(-/-) mice failed to function as effective antigen-presenting cells. Moreover, depletion of Ly6G(+) cells prolonged the survival of mice with developing gliomas. Human epidemiologic studies revealed that SNPs in IFNAR1 and IFNA8 are associated with significantly altered overall survival of patients with WHO grade 2 to 3 gliomas.


CONCLUSIONS
The novel Sleeping Beauty-induced murine glioma model led us to discover a pivotal role for the type 1 IFN pathway in antiglioma immunosurveillance and relevant human SNPs that may represent novel prognostic markers.
Fujita
Mitsugu
M
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Scheurer
Michael E
ME
Decker
Stacy A
SA
McDonald
Heather A
HA
Kohanbash
Gary
G
Kastenhuber
Edward R
ER
Kato
Hisashi
H
Bondy
Melissa L
ML
Ohlfest
John R
JR
Okada
Hideho
H
D056704:Adaptive Immunity; D000818:Animals; D001932:Brain Neoplasms / Q000191:economics* / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D054357:Chemokine CXCL10; D003713:Dendritic Cells / Q000276:immunology; D005910:Glioma / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015166:Monitoring, Immunologic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D054357:Chemokine CXCL10; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta
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