Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
J Immunother Cancer. 2021 Jul;9(7). doi: 10.1136/jitc-2021-002383.
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.
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, and experiments were performed to verify the correlation and explore the underlying mechanism.
We revealed that GTP cyclohydrolase 1 () expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. and o 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 () and thus enhanced the transcription of . 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.
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.
调节性 T 细胞（Tregs）大量浸润三阴性乳腺癌（TNBC），其浸润程度受到癌细胞代谢重编程的影响。本研究旨在鉴定与 TNBC 中 Tregs 浸润相关的内在肿瘤细胞代谢调节因子。
利用我们研究所的 RNA-seq 数据（n=360）和乳腺癌国际联合会 TNBC 队列的分子分类学数据（n=320），我们计算了每个样本中 Tregs 的丰度，并评估了基因表达水平与 Tregs 浸润之间的相关性。然后进行了 和 实验以验证相关性并探索潜在机制。
我们揭示了 GTP 环水解酶 1（GCH1）的表达与 Tregs 浸润呈正相关，高 GCH1 表达与 TNBC 患者总生存期缩短相关。 和 o 实验表明，GCH1 增加了 Tregs 的浸润，减少了细胞凋亡，并提高了程序性细胞死亡蛋白 1（PD-1）阳性细胞的比例。代谢组学分析表明，GCH1 过表达重编程了色氨酸代谢，导致细胞质中 L-5-羟色氨酸（5-HTP）积累，同时伴有色氨酸分解产物犬尿氨酸的积累和上清液中色氨酸的减少。随后，芳香烃受体（aryl hydrocarbon receptor，AHR）被 5-HTP 激活，与吲哚胺 2,3-双加氧酶 1（IDO1）的启动子结合，从而增强了 IDO1 的转录。此外，用 2,4-二氨基-6-羟基嘧啶（DAHP）抑制 GCH1 可降低 IDO1 的表达，抑制肿瘤生长，并增强肿瘤对 PD-1 阻断免疫治疗的反应。
肿瘤细胞内源性 GCH1 通过代谢重编程和 IDO1 的上调诱导 TNBC 中的免疫抑制。DAHP 抑制 GCH1 可能成为 TNBC 的一种潜在免疫代谢策略。
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