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

Nabil Hajji, Juan Garcia-Revilla, Manuel Sarmiento Soto, Richard Perryman, Jake Symington, Chad C. Quarles, Deborah R. Healey, Yijie Guo, Manuel Luis Orta-Vázquez, Santiago Mateos-Cordero, Khalid Shah, John Bomalaski, Giulio Anichini, Andreas G. Tzakos, Timothy Crook, Kevin O’Neill, Adrienne C. Scheck, Jose Luis Venero, Nelofer Syed

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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

Original languageEnglish (US)
Article numbere142137
JournalJournal of Clinical Investigation
Volume132
Issue number6
DOIs
StatePublished - Mar 15 2022
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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