Lipid signalling enforces functional specialization of T-reg cells in tumours

Article

关键词: REGULATORY T;    DIFFERENTIATION;    INFLAMMATION;    MAINTENANCE;    PROGRAMS;    MICE;   

DOI  :  10.1038/s41586-021-03235-6

来源: SCIE

【 摘 要 】

Regulatory T cells (T-reg cells) are essential for immune tolerance(1), but also drive immunosuppression in the tumour microenvironment(2). Therapeutic targeting of T-reg cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in T-reg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral T-reg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)-a factor required for SREBP activity-in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-gamma and impaired function of intratumoral T-reg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of T-reg cells, and loss of FASN from T-reg cells inhibits tumour growth. Second, T-reg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signalsvia mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral T-reg cells. Our findings show that metabolic reprogramming enforces the functional specialization of T-reg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.

【 授权许可】

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