Lipid signalling enforces functional specialization of Treg cells in tumours
Authors and Affiliations
Authors and Affiliations
Seon Ah Lim1,3, Jun Wei1,3, Thanh-Long M. Nguyen1, Hao Shi1, Wei Su1, Gustavo Palacios1, Yogesh Dhungana1, Nicole M. Chapman1, Lingyun Long1, Jordy Saravia1, Peter Vogel2 & Hongbo Chi1,*
1Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA. 2Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA. 3These authorscontributed equally: Seon Ah Lim, Jun Wei.
*Corresponding author
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.
1. 논문관련 분야의 소개, 동향, 전망을 설명, 연구과정에서 생긴 에피소드
항암 면역치료는 수술, 화학적 치료, 방사선 치료의 한계를 극복하기 위하여 개발된 현재 주목받고 있는 우수한 치료법 중 하나이지만 종양 미세환경으로 인해 여전히 치료의 한계가 있다는 문제점을 가지고 있습니다. 따라서 효과적인 항암 면역치료를 위해서는 종양 미세환경을 조절하여 그 항암효과를 높이고자 하는 치료 전략이 중요합니다. 특히나 종양 미세 환경에 존재하는 조절 T (Treg)...