THE PROTO-ONCOGENE FYN INHIBITS THE ANTI-GLIOBLASTOMA IMMUNE RESPONSE

Comba, A.; Dunn, P. J.; Argento, A. E.; Kadiyala, P.; Ventosa, M.; Zamler, D. B.; Patel, P.; Zhao, L.; Nunez, F. J.; Castro, M. G.; Lowenstein, P. R.

doi:10.1101/608505

bioRxiv · 10.1101/608505

THE PROTO-ONCOGENE FYN INHIBITS THE ANTI-GLIOBLASTOMA IMMUNE RESPONSE

Comba, A.·Dunn, P. J.·Argento, A. E.·Kadiyala, P.·Ventosa, M.·Zamler, D. B.·Patel, P.·Zhao, L.·Nunez, F. J.·Castro, M. G.·Lowenstein, P. R.

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Abstract

BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYNs role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion. MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME. ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8-/- and CD4-/- immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME. ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies. Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity. Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

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Comba, A., Dunn, P. J., Argento, A. E., Kadiyala, P., Ventosa, M., Zamler, D. B., Patel, P., Zhao, L., Nunez, F. J., Castro, M. G., Lowenstein, P. R.. 2019-04-13. THE PROTO-ONCOGENE FYN INHIBITS THE ANTI-GLIOBLASTOMA IMMUNE RESPONSE. https://doi.org/10.1101/608505

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