Blocking purine synthesis in cancer promotes response to immunotherapy

Nucleotide imbalance promotes mutagenesis in multiple types of cancer. We have previously shown that nucleotide imbalance favoring pyrimidines leads to mutational bias, which promotes the generation of immunogenic neoantigens that respond to ICT. We now find that tumors with high purine bias demonstrate a novel asymmetric genomic signature, consisting of transversion mutations manifested at the DNA, RNA, and protein level. This metabolic alteration leads to presentation of less immunogenic neoantigens and to decreased response to immune checkpoint inhibitors independent of mutational load. Reversing the nucleotide imbalance to favor pyrimidines improves the response to immunotherapy. Our data firmly establish that beyond mutational load and tumor heterogeneity, purine/pyrimidine bias is a strong determinant of the response to immunotherapy. Importantly, our findings suggest that we can metabolically manipulate tumor mutations to improve patients’ response to immunotherapy. Citation Format: Ayelet Erez, Eytan Ruppin, Rom Keshet, Joo Sang Lee. Blocking purine synthesis in cancer promotes response to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA21.