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
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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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 4

Arginine deprivation increases recruitment of microglia into tumors and enhances their activity and phagocytic phenotype.

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Arginine deprivation increases recruitment of microglia into tumors and ...
(A) Immunohistochemical evaluation of microglial/macrophage infiltration using Iba-1 staining on the contralateral nontumor side (green box), tumor edge (blue box), and intratumor (red box). (B) Intratumoral microglia occupancy. (C and D) Characterization of microglial phagocytic capacity using H&E and Oil red O staining of tumor sections and quantification of lipid bodies. (E and F) Assessment of the level of ˙NO production by microglia by 3-nitrotyrosine (3-NT) and Iba-1 staining of tumor sections. Iba-1 (green), 3-NT (red), colocalization of Iba-1 and 3-NT (yellow). Results were obtained from 5 animals per group. Note in the combined treatment group, analysis was carried out on the single animal showing evidence of tumor. Scale bars: 50 μm. Data were analyzed using 1-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001.