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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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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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