FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

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. FYN’s 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.

NLRC5: A Potential Target for Central Nervous System Disorders

“…NLRC5, an IFN-related gene, has been shown to be associated with overall survival of GBM patients (14). IFN-g is mainly produced by T and NK cells It can induce a positive feedback in the STAT1 pathway that triggers the expression and activation of STAT1 and other downstream genes, such as NLRC5, CIITA, and TAP1, and increases the immune response in the tumor microenvironment (5,15). In vivo genetic knockdown of the proto-oncogene Fyn can induce changes in IFN-g secretion, promote the overexpression of STAT1 and its downstream genes, and further increase the antitumor immune response in immunocompetent mouse glioma models, which significantly extends survival (15).…”

“…IFN-g is mainly produced by T and NK cells It can induce a positive feedback in the STAT1 pathway that triggers the expression and activation of STAT1 and other downstream genes, such as NLRC5, CIITA, and TAP1, and increases the immune response in the tumor microenvironment (5,15). In vivo genetic knockdown of the proto-oncogene Fyn can induce changes in IFN-g secretion, promote the overexpression of STAT1 and its downstream genes, and further increase the antitumor immune response in immunocompetent mouse glioma models, which significantly extends survival (15). In addition, upregulation of the lncRNA secretory carrier membrane protein 1 (SCAMP1), which functions as an oncogene in glioma cells, significantly promotes glioma cell proliferation, migration, and invasion and inhibits apoptosis (13).…”

“…It was previously reported that NLRC5 [NLR family caspase recruitment domain (CARD) containing 5, also known as NOD4, NOD27, and CLR16.1] accounts for a large proportion of the NLR family, which can modulate immune responses in the context of many human diseases, such as liver disease, renal disease, rheumatoid arthritis, and heart disease, by regulating nuclear factor-kB (NF-kB), type I interferon (IFN-1), inflammasome signaling pathways and the expression of the major histocompatibility complex (MHC) I genes (3)(4)(5). However, in recent years, studies have found that NLRC5 is also associated with CNS infection (CNSI) (6)(7)(8)(9), neuronal development (10), and neuropsychiatric disorders, such as cerebral ischemia/reperfusion (I/R) injury (11,12), glioma (13)(14)(15), multiple sclerosis (MS) (16), epilepsy (17), schizophrenia (SCZ), and bipolar disorder (BD) (18,19).…”