Tregs promote M2-like TAM activity by limiting the secretion of IFNγ by CD8+ T cells.
Major finding: Tregs promote M2-like TAM activity by limiting the secretion of IFNγ by CD8+ T cells.
Mechanism: CD8+ T cell–secreted IFNγ inhibits SREBP1-dependent lipid metabolism in M2-like TAMs.
Impact: Inhibition of SREBP1 in TAMs may sensitize tumors to immune checkpoint blockade.
Regulatory T cells (Treg) play a key role in the immunosuppressive tumor microenvironment (TME). Ablation of Tregs results in tumor regression and major changes in cell populations within the TME but can also lead to severe autoimmune and inflammatory outcomes. Therefore, perturbation of mechanisms downstream of Tregs might augment the efficacy of immunotherapy without the need to directly target Tregs. Building on previous observations that the neuropilin-1 (NRP1)–semaphorin 4a axis mediates effects of Tregs in the TME and that mice with Treg-restricted depletion of NRP1 cleared tumors without autoimmunity or inflammation, Liu and colleagues showed that unlike dysfunctional NRP1-deficient Tregs, wild-type Tregs promoted the accumulation of M2-like tumor associated macrophages (TAM) in the TME and enhanced their protumor gene expression signature and metabolic function. Mechanistically, Tregs promoted M2-like TAM activity by inhibiting the secretion of IFNγ by CD8+ T cells, which would otherwise limit M2-like TAM development and function. In addition, Tregs promoted M2-like TAM function by enhancing SREBP1-dependent fatty-acid synthesis and metabolic fitness indirectly through CD8+ T cells. These results suggest a potential advantage of targeting fatty-acid synthesis in M2-like TAMs by inhibiting SREBP1 in combination with immune checkpoint blockade to enhance CD8+ activation. Indeed, combination treatment with the SREBP1 inhibitor fatostatin and anti–PD-1 showed improved efficacy in comparison to each treatment alone in an anti–PD-1–resistant mouse model. Targeting lipid metabolism in TAMs may therefore sensitize tumors to immune checkpoint blockade therapy.
Liu C, Chikina M, Deshpande R, Menk AV, Wang T, Tabib T, et al. Treg cells promote the SREBP1-dependent metabolic fitness of tumor-promoting macrophages via repression of CD8+ T cell-derived interferon-γ. Immunity 2019 Jul 23 [Epub ahead of print].
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