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

• Published in: Immunity (Cambridge, Mass.) Vol. 51; no. 2; pp. 381 - 397.e6
• Main Authors: Liu, Chang, Chikina, Maria, Deshpande, Rahul, Menk, Ashley V., Wang, Ting, Tabib, Tracy, Brunazzi, Erin A., Vignali, Kate M., Sun, Ming, Stolz, Donna B., Lafyatis, Robert A., Chen, Wei, Delgoffe, Greg M., Workman, Creg J., Wendell, Stacy G., Vignali, Dario A.A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-08-2019; Elsevier Limited
• Subjects: Animals; Cancer; Cancer immunotherapy; Carcinogenesis; CD8 antigen; CD8+ T cell-derived interferon-γ; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Differentiation; Fatty acids; Fatty Acids - metabolism; Fitness; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; Homeostasis; Immune checkpoint; Immune Evasion; Immune system; Immunotherapy; Interferon; Interferon-gamma - metabolism; Laboratory animals; Lipid metabolism; Lipids; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - metabolism; Melanoma - immunology; Melanoma, Experimental; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Neoplasms, Experimental - immunology; Neuropilin; Neuropilin-1 - genetics; Reproductive fitness; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterol regulatory element-binding protein; Survival analysis; T-Lymphocytes, Regulatory - immunology; Th2 Cells - immunology; Transcription; Treg cells; Tumor Microenvironment; tumor-promoting macrophages; Tumors; γ-Interferon; Treg cells; tumor-promoting macrophages; CD8+ T cell-derived interferon-γ; CD8(+) T cell-derived interferon-γ
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2019.06.017

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.
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•Treg cells shape the intratumoral immune landscape required for tumor immune evasion•Treg cells promote an M2-like TAM phenotype indirectly by suppressing CD8+ T cells•CD8+ T cell-derived IFNγ blocks SREBP1-dependent fatty acid metabolism in TAMs•SREBP1 inhibition augments the efficacy of immune checkpoint blockade
Treg cells contribute to tumor immune evasion, but the mechanisms by which they exert this effect have not been fully elucidated. Liu et al. find that Treg cells repress CD8+ T cell-derived IFNγ to sustain immunosuppressive tumor-associated macrophages by promoting SREBP1-dependent lipid metabolism, thereby orchestrating tumor-associated immunosuppression. Targeting Treg cells or their modulation of TAM lipid metabolism may improve cancer immunotherapy.