Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression.

BACKGROUND: Metabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to regulate breast cancer progression are not fully understood. We identify hypoxia-mediated suppression of pyruvate carboxylase (PC), and subsequent induction of lactate production, as a metabolic regulator of immunosuppression. METHODS: We used qPCR, immunoblot, and reporter assays to characterize repression of PC in hypoxic primary tumors. Steady state metabolomics were used to identify changes in metabolite pools upon PC depletion. In vivo tumor growth and metastasis assays were used to evaluate the impact of PC manipulation and pharmacologic inhibition of lactate transporters. Immunohistochemistry, flow cytometry, and global gene expression analyzes of tumor tissue were employed to characterize the impact of PC depletion on tumor immunity. RESULTS: PC is essential for metastatic colonization of the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This effect was only observed in immune competent animals, supporting the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments, we demonstrate that hypoxia potently downregulated PC. In the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors. CONCLUSIONS: We present a dimorphic role for PC in primary mammary tumors vs. pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immunity.

Effects of Acute Exercise on Anxiety Ratings in Patients With Coronary Heart Disease and Elevated Anxiety.

PURPOSE: To explore individual differences in state anxiety following a single, acute bout of aerobic exercise among anxious patients with diagnosed coronary heart disease (CHD). METHODS: One hundred eighteen CHD patients with elevated symptoms of anxiety enrolled in the UNderstanding the Benefits of Exercise and Escitalopram in Anxious Patients WIth coroNary Heart Disease (UNWIND) clinical trial rated their level of anxiety using a 100-mm visual analog scale before and after a symptom-limited exercise treadmill test. A number of exercise (eg, peak oxygen uptake, exercise duration, maximum heart rate, anaerobic threshold) and psychological variables were examined as potential predictors of exercise response. Changes in anxiety and their association with psychological variables were examined using general linear models. RESULTS: Fifty patients (42%) rated a reduction in anxiety relative to their pre-exercise ratings following the exercise treadmill test. While a number of factors were examined, the only factor that distinguished those individuals who reported a reduction in anxiety symptoms compared with those who either remained the same or actually reported an increase in anxiety was a higher pre-exercise visual analog scale anxiety rating. No differences were observed as a function of sex, severity of trait anxiety, the presence of an anxiety disorder, exercise test duration, or age. CONCLUSIONS: Although many variables were examined, only higher baseline anxiety distinguished those who showed a reduction in their visual analog scale ratings from those whose anxiety remained the same or got worse. The extent to which the response to acute exercise predicts the anxiolytic effects of chronic exercise needs further study.