Lipid signalling enforces functional specialization of T.sub.reg cells in tumours.

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From: Nature(Vol. 591, Issue 7849)
Publisher: Nature Publishing Group
Document Type: Report
Length: 17,086 words
Lexile Measure: 1710L

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Abstract :

Regulatory T cells (T.sub.reg cells) are essential for immune tolerance.sup.1, but also drive immunosuppression in the tumour microenvironment.sup.2. Therapeutic targeting of T.sub.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.sub.reg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral T.sub.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.sub.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.sub.reg cells, and loss of FASN from T.sub.reg cells inhibits tumour growth. Second, T.sub.reg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral T.sub.reg cells. Our findings show that metabolic reprogramming enforces the functional specialization of T.sub.reg cells in tumours, pointing to new ways of targeting these cells for cancer therapy. Identification of a metabolic checkpoint involving lipid signalling that is specific to regulatory T cells (T.sub.reg cells) in the tumour microenvironment raises the possibility of targeting this checkpoint for treatment of cancer.

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Gale Document Number: GALE|A660673918