Abstract IA02: Regulating amino acid metabolism can improve response to immunotherapy

Abstract

Abstract Aberrant expression of urea cycle enzymes occurs in multiple types of cancer. We have previously demonstrated that the urea cycle enzyme ASS1 is downregulated in different tumor types to increase the availability of its substrate aspartate for pyrimidine synthesis, supporting cell proliferation. Therapeutically, we demonstrated that high pyrimidine to purine ratio improves response to immunotherapy. Interestingly, in several prevalent types of cancer ASS1 expression is upregulated for a yet unknown metabolic benefit that associates with poor patients’ prognosis. We now find that ASS1 expression in cancer provides a survival advantage in nutrient deficiency states by generating NO that activates gluconeogenesis. The increase in gluconeogenic flux increases serine levels and leads to a nucleotide imbalance promoting pyrimidine to purine transversion mutations. Consequently, cancers with high ASS1 expression are less immunogenic. Reversing the nucleotide imbalance to favor pyrimidines leads to better response to immunotherapy. Our data establish ASS1 expression as a metabolic survival mechanism under nutrient deprivation that may also serve as a strong determinant of the immune response. Importantly, our findings suggest that we can metabolically regulate tumor mutations to improve patients’ responsiveness to immunotherapy. Citation Format: Ayelet Erez, Eytan Ruppin. Regulating amino acid metabolism can improve response to immunotherapy [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA02.