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Immunity. 2019 Jul 13. pii: S1074-7613(19)30287-0. doi: 10.1016/j.immuni.2019.06.017. [Epub ahead of print]

Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ.

Author information

1
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
2
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
3
Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA 15261, USA.
4
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.
5
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
6
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
7
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
8
Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Pharmacology and Chemical Biology, Clinical Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
9
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA. Electronic address: dvignali@pitt.edu.

Abstract

Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin-1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity, and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.

KEYWORDS:

CD8(+) T cell-derived interferon-γ; Treg cells; tumor-promoting macrophages

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