Pegylated arginine deiminase and PD-1/PD-L1 blockade in the treatment of ASS1-deficient cancers
Khadeir R1, Locke M1, Thaung C2, Lemoine NR1, Bomalaski J3, Martin SA1, Sheaff MT1, Quezada S4, Szlosarek PW1 1Center for Molecular Oncology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK; 2Institute of Ophthalmology, UCL, London EC1V 9EL, UK 3Polaris Pharma, San Diego, CA, USA; 4UCL Cancer Institute, London WC1E 6BPCMR
Poor prognosis cancers lacking the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) are sensitive to arginine deprivation therapy. Nevertheless, resistance occurs in part due to ASS1 re-expression reducing the efficacy of arginine depletors in the clinic. Here, we report a novel immunometabolic therapy for ASS1-negative tumors exploiting this limitation. Tumoral ASS1 induction via prolonged treatment with the arginine lowering agent pegylated arginine deiminase (ADI-PEG20) or via gene transfection modulated PD-L1 expression eliciting a type I interferon (IFN) gene signature in malignant pleural mesothelioma (MPM) and uveal melanoma (UM) cell lines. A statistically significant correlation between constitutive ASS1 and PD-L1 expression was noted in primary MPM (p<0.001) and UM by immunohistochemistry (IHC). Moreover, ADI-PEG20 treatment induced transcription factor X-box binding protein 1 (XBP1) to release IFN-α and -β thereby triggering PD-L1 expression in the MPM and UM tumor cell lines by 24hrs and declining to basal levels by 48hrs. Whereas JAK/STAT inhibition prevented the increase in PD-L1, it was sustained with blockade of suppressor of cytokine signaling (SOCS). Finally, we showed that the combination of PD-1 or PD-L1 blockade with ADI-PEG20 abrogated tumorigenesis in an immunocompetent ASS1 negative and PD-L1 negative fibrosarcoma murine model in which PD-1 or PD-L1 inhibition alone had limited efficacy. Anti-PD1 or anti-PD-L1 and ADI-PEG20 induced a T cell-rich and macrophage-poor infiltrate with an increase in tumoral ASS1 and PD-L1 expression in the tumor. Based on these data clinical trials of ADI-PEG20 and PD-1/PD-L1 immune checkpoint blockade have commenced in arginine-dependent tumors.
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