Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors.
Rom KeshetJoo Sang LeeLital AdlerMuhammed IraqiYarden AriavLisha Qiu Jin LimShaul LernerShiran RabinovichRoni OrenRotem KatzirHila Weiss TishlerNoa StettnerOmer GoldmanHadas LandesmanSivan GalaiYael KupermanYuri KuznetsovAlexander BrandisTevi MehlmanSergey MalitskyMaxim ItkinS Eleonore KoehlerYongmei ZhaoKeyur TalsaniaTsai-Wei ShenNir PeledIgor UlitskyAngel PorgadorEytan RuppinAyelet ErezPublished in: Nature cancer (2020)
Argininosuccinate synthase (ASS1) downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with poor patient prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by c-MYC, providing survival benefit by increasing nitric oxide synthesis and activating the gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase by S-nitrosylation. The resulting increased flux through gluconeogenesis enhances serine, glycine and subsequently purine synthesis. Notably, high ASS1-expressing breast cancer mice do not respond to immune checkpoint inhibitors and patients with breast cancer with high ASS1 have more metastases. We further find that inhibiting purine synthesis increases pyrimidine to purine ratio, elevates expression of the immunoproteasome and significantly enhances the response of autologous primary CD8 + T cells to anti-PD-1. These results suggest that treating patients with high-ASS1 cancers with purine synthesis inhibition is beneficial and may also sensitize them to immune checkpoint inhibition therapy.
Keyphrases
- poor prognosis
- cell proliferation
- nitric oxide
- signaling pathway
- binding protein
- squamous cell carcinoma
- blood pressure
- bone marrow
- stem cells
- case report
- long non coding rna
- cell therapy
- metabolic syndrome
- mesenchymal stem cells
- blood glucose
- papillary thyroid
- high fat diet induced
- cancer therapy
- squamous cell
- wild type