探索三阴性乳腺癌免疫逃逸代谢机制
调节型T淋巴细胞具有强大的免疫抑制能力，可及时有效地结束免疫反应，防止免疫反应对机体自身造成过度损害。不过，三阴性乳腺癌等恶性肿瘤细胞通过代谢重编程，可引起大量调节型T淋巴细胞浸润，从而逃避被杀伤型T淋巴细胞消灭。明确三阴性乳腺癌被调节型T淋巴细胞浸润的代谢重编程机制，将有助于提高免疫治疗效果。
2021年7月19日，《英国医学杂志》旗下《癌症免疫治疗杂志》在线发表复旦大学附属肿瘤医院魏金丽、邬思雨、杨云松、肖毅、金希、徐晓恩、胡欣、李大强、江一舟、邵志敏等学者的研究报告，探索了三阴性乳腺癌被调节型T淋巴细胞浸润的代谢重编程机制。
该研究首先利用复旦大学附属肿瘤医院360例和国际乳腺癌分子分类联盟（METABRIC）320例三阴性乳腺癌标本的核糖核酸（RNA）测序数据，计算每个标本的调节型T淋巴细胞丰度，并分析基因表达水平与调节型T淋巴细胞浸润之间的相关性。随后，进行体内和体外实验对相关性进行验证，并探索其潜在机制。
结果发现，三磷酸鸟苷环化水解酶GCH1表达水平与调节型T淋巴细胞浸润丰度成正比，GCH1高表达与低表达的三阴性乳腺癌患者相比，总生存率显著较低。
体内和体外实验表明，GCH1可增加调节型T淋巴细胞浸润、减少细胞凋亡，并提高杀伤型T淋巴细胞表面程序性死亡受体PD-1阳性比例。
代谢组学分析表明，GCH1过表达可对色氨酸代谢进行重新编程，引起左旋5-羟色氨酸（5-HTP）蓄积于细胞质，伴随上清液犬尿酸原增加和色氨酸减少。随后，被5-HTP激活的芳烃受体（AHR）与吲哚胺2,3-双加氧酶1（IDO1）启动子结合，从而增强IDO1转录。
此外，2,4-二氨基-6-羟基嘧啶（DAHP）可抑制GCH1、减少IDO1表达、削弱肿瘤生长、增强PD-1抑制剂对肿瘤的免疫治疗效果。而且，DAHP是一种非常低廉的药品原料，主要用于生产降压药敏乐啶、抗贫血药叶酸等。
因此，该研究结果表明，肿瘤细胞内GCH1通过代谢重编程和上调IDO1可诱导三阴性乳腺癌被调节型T淋巴细胞浸润，从而抑制免疫杀伤，引起免疫逃逸。DAHP对GCH1的抑制作用可显著增强PD-1抑制剂对三阴性乳腺癌的免疫治疗效果，有望成为三阴性乳腺癌免疫代谢治疗的新策略，故有必要进一步开展临床研究进行验证。
相关链接
J Immunother Cancer. 2021 Jul 19;9(7):e002383.
GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer.
Jin-Li Wei, Si-Yu Wu, Yun-Song Yang, Yi Xiao, Xi Jin, Xiao-En Xu, Xin Hu, Da-Qiang Li, Yi-Zhou Jiang, Zhi-Ming Shao.
Fudan University Shanghai Cancer Center, Shanghai, China.
PURPOSE: Regulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.
EXPERIMENTAL DESIGN: Using the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.
RESULTS: We revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.
CONCLUSIONS: Tumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.
DOI: 10.1136/jitc-2021-002383