Metabolism drives macrophage heterogeneity in the tumor microenvironment
Shasha Li,
Jiali Yu,
Amanda Huber,
Ilona Kryczek,
Zhuwen Wang,
Long Jiang,
Xiong Li,
Wan Du,
Gaopeng Li,
Shuang Wei,
Linda Vatan,
Wojciech Szeliga,
Arul M. Chinnaiyan,
Michael D. Green,
Marcin Cieslik,
Weiping Zou
Affiliations
Shasha Li
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI, USA
Jiali Yu
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Amanda Huber
Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Ilona Kryczek
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Zhuwen Wang
Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Long Jiang
Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Xiong Li
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Wan Du
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Gaopeng Li
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Shuang Wei
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Linda Vatan
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Wojciech Szeliga
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA
Arul M. Chinnaiyan
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan School of Medicine, Ann Arbor, MI, USA
Michael D. Green
Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
Marcin Cieslik
Department of Computational Medicine and Bioinformatics, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Corresponding author
Weiping Zou
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA; Corresponding author
Summary: Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.
