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A novel oral arginase 1/2 inhibitor enhances the antitumor effect of PD-1 inhibition in murine experimental gliomas by altering the immunosuppressive environment.

ABSTRACT: Malignant gliomas are common and aggressive primary brain tumors which are incurable by conventional therapies. Immunotherapy with the immune checkpoint inhibitors is not effective due to the highly immunosuppressive tumor microenvironment (TME). Clinical and experimental data show upregulation of Arginase1 (ARG1) expression in rodent and human malignant gliomas. The elevated ARG1 activity leads to depletion of L-arginine required for proliferation of T lymphocytes and natural killer cells. Inhibition of ARG1 in TME may unblock T cell proliferation and activate effective antitumor responses. To explore an antitumor potential of ARG1 inhibition, first we analyzed bulk and single cell RNA sequencing (scRNA-seq) data from human and murine gliomas, and found upregulation of ARG1 expression in malignant gliomas, both in tumor cells and in tumor infiltrating microglia, monocytes/macrophages. We employed the novel, selective arginase inhibitor - OAT-1746 to interfere with microglia-induced glioma invasion in microglia-glioma co-cultures. We determined its antitumor efficacy as a monotherapy and in combination with immunotherapy. In a Matrigel invasion assay OAT-1746 blocked microglia-dependent invasion of U87-MG and LN18 glioma cells better than reference compounds, without affecting cell viability. OAT-1746 effectively crossed the BBB and increased arginine levels in brains of GL261 glioma bearing mice. The compound reduced glioma growth and increased antitumor effects of the anti-PD-1 antibody. Treatment with OAT-1746 modified TME as demonstrated by profound transcriptomic changes visualized by RNA sequencing. Our findings provide the evidence that inhibition of ARG1 in tumor cells and myeloid cells in TME abolishes the immunosuppressive reprograming of myeloid cells and improves the efficacy of immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE173865 | GEO | 2021/08/24

REPOSITORIES: GEO

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Project description:Murine BV2 microglia cells were transfected either with siRNA negative control or siRNA against caspase-3 for 48h. Later on some the of the BV2 transfected cells were co-cultured with C6 glioma cells during 6h. We used the SA Biosciences Mouse Wound Healing PCR Array (PAMM-121Z) to quantitate gene expression of relevant genes related to the wound healing process Glioma cells recruit and exploit microglia, resident immune cells of the brain, for their proliferation and invasion capability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype remains elusive. Here, we report that glioma-induced microglia conversion is coupled to a reduction of basal microglial caspase-3 activity, increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and demonstrate that caspase-3 inhibition regulates microglial tumor-supporting function. Further, we identified nitric oxide synthase-2 (NOS2) activity originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to reduction in both microglia recruitment and tumor expansion, whereas depletion of the microglial caspase-3 gene promoted tumor growth. This study provides evidence that the inhibition of Trx2-mediated denitrosylation of SNO-procaspase-3 is part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells. qPCR gene expression profiling. Three independent experiments of siControl BV2 monoculture, siCaspase3 BV2 monoculture, siControl BV2 cocultured 6h with C6 glioma cells and siCaspase3 BV2 cocultured 6h with C6 glioma cells. Equal amount total RNA from each culture was used for the gene expression analysis. Please note that the raw data for three independent experiments (prior to averaging the data) is provided in the 'Raw_Data_File_with_the_Ct_values_for_3_indep_experiments.txt'.

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A novel oral arginase 1/2 inhibitor enhances the antitumor effect of PD-1 inhibition in murine experimental gliomas by altering the immunosuppressive environment.

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