2. Academic Validation
  3. Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression

Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression

  • Breast Cancer Res. 2024 Jun 7;26(1):96. doi: 10.1186/s13058-024-01854-1.
Michael F Coleman # 1,  Eylem Kulkoyluoglu Cotul # 2,  Alexander J Pfeil 1,  Emily N Devericks 1,  Muhammad H Safdar 2,  Marvis Monteiro 2,  Hao Chen 2,  Alyssa N Ho 1,  Numair Attaar 1,  Hannah M Malian 1,  Violet A Kiesel 1,  Alexis Ramos 3,  Matthew Smith 3,  Heena Panchal 3,  Adam Mailloux 3 4,  Dorothy Teegarden 5 6,  Stephen D Hursting 1 7 8,  Michael K Wendt 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
  • 3 Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
  • 4 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
  • 5 Purdue University Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
  • 6 Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
  • 7 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 8 Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.
  • 9 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. mkwendt@uiowa.edu.
  • 10 Purdue University Institute for Cancer Research, Purdue University, West Lafayette, IN, USA. mkwendt@uiowa.edu.
  • 11 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. mkwendt@uiowa.edu.
  • 12 Department of Internal Medicine, University of Iowa, Iowa City, IA, USA. mkwendt@uiowa.edu.
  • # Contributed equally.
PMID: 38849928 DOI: 10.1186/s13058-024-01854-1
Abstract

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.

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