Lipid signalling enforces functional specialization of Treg cells in tumours

Seon Ah Lim, Jun Wei, Thanh-Long M. Nguyen, Hao Shi, Wei Su, Gustavo Palacios, Yogesh Dhungana, Nicole M. Chapman, Lingyun Long, Jordy Saravia, Peter Vogel and Hongbo Chi ()
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Seon Ah Lim: St Jude Children’s Research Hospital
Jun Wei: St Jude Children’s Research Hospital
Thanh-Long M. Nguyen: St Jude Children’s Research Hospital
Hao Shi: St Jude Children’s Research Hospital
Wei Su: St Jude Children’s Research Hospital
Gustavo Palacios: St Jude Children’s Research Hospital
Yogesh Dhungana: St Jude Children’s Research Hospital
Nicole M. Chapman: St Jude Children’s Research Hospital
Lingyun Long: St Jude Children’s Research Hospital
Jordy Saravia: St Jude Children’s Research Hospital
Peter Vogel: St Jude Children’s Research Hospital
Hongbo Chi: St Jude Children’s Research Hospital

Nature, 2021, vol. 591, issue 7849, 306-311

Abstract: Abstract Regulatory T cells (Treg cells) are essential for immune tolerance1, but also drive immunosuppression in the tumour microenvironment2. Therapeutic targeting of Treg 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 Treg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral Treg 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-γ and impaired function of intratumoral Treg 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 Treg cells, and loss of FASN from Treg cells inhibits tumour growth. Second, Treg 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 Treg cells. Our findings show that metabolic reprogramming enforces the functional specialization of Treg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.

Date: 2021
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DOI: 10.1038/s41586-021-03235-6

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