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Suppression of Pyruvate carboxylase in E0771 tumors [in vivo]

ABSTRACT: Metabolic reprogramming an immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Conversely, PC may be dispensable in some cells in the TME, with loss of PC associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. PC supports metastatic colonization of the lungs; however, depletion of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC suppression is common in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high resolution respirometry, and extracellular flux analysis, we show that PC-depleted cells produce more lactate and undergo less oxidative phosphorylation than scramble controls. Finally, we identify lactate metabolism as a targetable dependency of PC-depleted cells, which is sufficient to restore T cell populations to the TME of PC-depleted tumors. Taken together these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight PC directed tumor metabolism is a nexus of tumor progression and antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE199829 | GEO | 2023/12/29

REPOSITORIES: GEO

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Suppression of Pyruvate carboxylase in E0771 tumors [in vivo]

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