Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to suppress HER2 + breast cancer.

Abstract

Background: Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing sepiapterin (SEP), the endogenous precursor of tetrahydrobiopterin (BH_4, the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we tested our hypothesis that a long-term administration of SEP to individuals susceptible to HER2-positive mammary tumor would protect them against tumor occurrence.

Methods: We administered SEP, in comparison to control DMSO, to MMTV-neu mice susceptible to HER2-positive mammary tumors for 8 months starting at their pre-pubertal stage. We monitored tumor onsets to determine the rate of tumor-free survival. After 8 months of treatment, we grouped animals into DMSO treatment with or without tumors and SEP treatment with or without tumors. We analyzed blood metabolites, PBMC, and bone marrow of DMSO vs. SEP treated animals.

Results: We found that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively suppressed tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention.

Conclusions: These findings suggest the possible roles of the SEP/BH₄/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.