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 10

Immunological assessment of CT-2A tumors in mice treated with ADI-PEG20 combined with ionizing radiation.

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Immunological assessment of CT-2A tumors in mice treated with ADI-PEG20 ...
(A) Representative H&E images of mouse brains at the mid time point and at time of death/harvest. (B) Representative GFAP staining of brains in combined treatment group showing contralateral and tumor region at late harvest time point. Time points: Early, 5 days after implantation and before treatment; Mid, 14 days after implantation and after 1 round of treatment; Late, 16 (ADI animals) and 18 days (all other groups) after implantation and after 2 rounds of treatment. DAPI was used as a nuclear counter stain (blue). Scale bars in E: 430 μm (top, middle); 170 μm (bottom).