Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

Abstract

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that
\nthe efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent
\nADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this
\ncombination led to durable and complete radiological and pathological response, with extended disease-free survival in
\nan orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular
\nsensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO)
\nand hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration
\ninto tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor)
\nphenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits
\nconsideration for early evaluation in clinical trials.