Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Kadiyala, P.; Carney, S. V.; Gauss, J. C.; Garcia-Fabiani, M.; Nunez, F.; Nunez, F. M.; Alghamri, M.; Liu, Y.; Yu, M.; Li, D.; Edwards, M.; Moon, J. J.; Schwendeman, A.; Lowenstein, P. R.; Castro, M.

doi:10.1101/2020.05.11.086371

bioRxiv · 10.1101/2020.05.11.086371

Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

Kadiyala, P.·Carney, S. V.·Gauss, J. C.·Garcia-Fabiani, M.·Nunez, F.·Nunez, F. M.·Alghamri, M.·Liu, Y.·Yu, M.·Li, D.·Edwards, M.·Moon, J. J.·Schwendeman, A.·Lowenstein, P. R.·Castro, M.

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Abstract

Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in -thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts -ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8+T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients. Brief SummaryInhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity.

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Kadiyala, P., Carney, S. V., Gauss, J. C., Garcia-Fabiani, M., Nunez, F., Nunez, F. M., Alghamri, M., Liu, Y., Yu, M., Li, D., Edwards, M., Moon, J. J., Schwendeman, A., Lowenstein, P. R., Castro, M.. 2020-05-12. Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity. https://doi.org/10.1101/2020.05.11.086371

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