IMMU-06. ABSENCE OF THE AMINO ACID STRESS-SENSOR GCN2 REDUCES SUPPRESSIVE EFFECTS OF MDSCs IN GLIOMA
Year: 2018
Type: conference-abstract
Abstract: Regulation of nutrient availability is a critical way by which tumors exert their immunosuppressive effects on the host. The glioblastoma microenvironment, in particular, is enriched in expression of indoleamine 2,3- dioxygenase 1 (IDO1), which depletes tryptophan from the microenvironment. Upon depletion of tryptophan, the amino acid stress kinase, general control non-derepressible 2 (GCN2), inhibits general protein synthesis, and upregulates a number of genes to promote the cellular survival. In this study, we explored the effects of a deficiency of the GCN2 pathway on infiltrating immune cells in the context of the glioma. Interestingly after GL-261 (Glioma mouse model cell line) injections in GCN2 knock out (KO), and wild type (WT) mice, GCN2 KO mice survived significantly (pvalue:0.0066) longer compared to WT mice. In-vivo flow cytometric analyses of these mice, showed significant reduction in CD45hiCD11b+ (myeloid cell marker) and Ly6C (monocytic MDSC marker) population in GCN2 KO mice. To study the mechanisms responsible for this, we generated in-vitro bone-marrow-derived MDSCs from both WT and GCN2KO mice. Surprisingly, the in-vitro T-cell suppressive effects of GCN2 KO MDSCs were significantly attenuated, with a decrease in arginase-1 (Arg-1) expression as a potential mechanism for this observation. To validate this phenomena in-vivo, we injected GCN2 KO and WT mice with GL-261 tumor cells, and after 18 days post tumor injection, we isolated Gr-1 (pan-MDSC marker) positive cells from tumor bearing brains, and checked for Arg-1 level by RNA and protein. Our data, both by protein and RNA demonstrated significant reduction in Arg-1 levels. Importantly, ex-vivo isolated Gr-1 myeloid cells from tumor bearing brain of GCN2 KO and WT mice shows dramatically reduced suppressive capabilities. In conclusion, our data demonstrate the importance of GCN2 pathway on MDSC functionality, and provide insight on how amino acid sensing enzymes may regulate immunity in glioblastoma.
Source: Neuro-Oncology
Institution: Northwestern University
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2899571925