Treg cells promote the SREBP1-dependent metabolic fitness of suppressive intratumoral macrophages via repression of CD8+ T cell-derived interferon-γ

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-gamma(IFN[gamma]), 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. Freshly sorted CD45+ cells from B16 tumors implanted in Foxp3Cre-YFP or Nrp1L/LFoxp3Cre-YFP mice (female, 5 week of age) on day 14 post inoculation