Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors
Nabil Hajji, … , Jose Luis Venero, Nelofer Syed
Nabil Hajji, … , Jose Luis Venero, Nelofer Syed
Published February 3, 2022
Citation Information: J Clin Invest. 2022;132(6):e142137. https://doi.org/10.1172/JCI142137.
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Research Article Oncology

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 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.

Authors

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

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Figure 3

Eradication of GBM intracranial tumors, glial scar formation, and enhanced survival of mice induced by ADI-PEG20 in combination with ionizing radiation.

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Eradication of GBM intracranial tumors, glial scar formation, and enhanc...
(A–C) Bioluminescence imaging (BLI) of intracranial tumors in mice using an IVIS Lumina II and Living Image software starting from day 13 after injection of GL261-Luc2 tumor cells. (D) Kaplan-Meier survival graph. Median survival times were 27, 47, and 37 days for saline, ADI-PEG20, and ionizing radiation (IR) monotherapy, respectively. Animals treated with combined treatment remained healthy and tumor free beyond 1 year. These animals received IR for 8 weeks and ADI-PEG20 for 13 weeks, after which time treatments were stopped. (E) Two animals from this group were culled on day 140 and brain sections were stained with H&E and for GFAP, showing evidence of histologically apparent glial scarring at the tumor site. Scale bars: 430 μm (left); 200 μm (middle, right). Data were analyzed using 2-way ANOVA with Tukey’s multiple comparison test, and adjusted P values are reported. ***P < 0.001 (saline vs. ADI-PEG20) + IR; §§§P < 0.001 (ADI-PEG20 vs. ADI-PEG20 + IR); ###P < 0.001 (IR vs. ADI-PEG20 + IR).