脂肪代谢可影响乳腺癌免疫治疗效果
调节型T淋巴细胞对于人体免疫耐受是必不可少的，但是也可促进肿瘤微环境产生免疫抑制和免疫逃逸，从而削弱肿瘤免疫治疗效果。因此，为了针对肿瘤调节型T淋巴细胞进行靶向治疗，需要确定影响其功能的特殊机制。
2021年2月24日，全球自然科学三大旗舰期刊之首、英国《自然》正刊在线发表美国圣犹达（耶稣十二门徒之一）儿童研究医院的研究报告，发现脂质信号传导可促进肿瘤调节型T淋巴细胞功能特殊化。
该研究表明，抑制脂质合成和代谢信号传导，依赖于调节型T淋巴细胞的固醇调节元素结合蛋白（SREBP）产生有效抗肿瘤免疫应答，而不产生自身免疫毒性。
该研究还发现，对于人类乳腺癌或头颈部鳞状细胞癌，肿瘤调节型T淋巴细胞的SREBP活性显著较高。此外，这些细胞SREBP活性所需的SREBP裂解激活蛋白一旦缺失，可抑制肿瘤生长，并增强针对杀伤型T淋巴细胞表面程序性死亡蛋白的PD-1抑制剂免疫治疗效果。SREBP裂解激活蛋白缺失，可引起γ干扰素不受控制地产生、肿瘤内调节型T淋巴细胞功能障碍。
机制分析表明，SREBP裂解激活蛋白和SREBP信号传导可协同调节这些细胞脂质合成和受体抑制信号传导的细胞程序。首先，脂肪酸合成酶的脂肪酸从头合成有助于调节型T淋巴细胞功能成熟，而调节型T淋巴细胞缺失脂肪酸合成酶则可抑制肿瘤生长。其次，肿瘤调节型T淋巴细胞通过依赖于SREBP活性和甲羟戊酸代谢和蛋白质戊二烯化信号可增强PD-1编码基因表达。阻断PD-1或SREBP信号传导可导致肿瘤调节型T淋巴细胞磷脂酰肌醇激酶PI3K活化失调。
因此，该研究结果表明，脂质代谢重编程可增强肿瘤调节型T淋巴细胞功能特殊化，从而为针对这些细胞进行癌症靶向治疗开辟了新的道路。
Nature. 2021 Feb 24. Online ahead of print.
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, Hongbo Chi.
St Jude Children's Research Hospital, Memphis, TN, USA.
Regulatory T cells (Treg cells) are essential for immune tolerance, but also drive immunosuppression in the tumour microenvironment. 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.
DOI: 10.1038/s41586-021-03235-6