Peng Yaojun, Wang Lingxiong, Yang Juan, Wu Qiyan, Sun Xiaoxuan, Zhang Jinying, Yu Yanju, Zhang Liping, Gao Jie, Zhou Qing, Zhu Haiyan, Yin Fan
Department of Emergency, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
Medical School of Chinese People's Liberation Army (PLA), Beijing, China.
Front Pharmacol. 2024 Sep 16;15:1466779. doi: 10.3389/fphar.2024.1466779. eCollection 2024.
Inhibition of indolamine-2,3-dioxygenase 1 (IDO1) has been proposed as a promising strategy for cancer immunotherapy; however, it has failed in clinical trials. Macrophages in the tumor microenvironment (TME) contribute to immune escape and serve as potential therapeutic targets. This study investigated the expression pattern of IDO1 in TME and its impact on prognosis and therapeutic response of patients with esophageal squamous cell carcinoma (ESCC).
RNA sequencing data from 95 patients with ESCC from The Cancer Genome Atlas (TCGA) database were used to explore the prognostic value of IDO1. Bioinformatics tools were used to estimate scores for stromal and immune cells in tumour tissues, abundance of eight immune cell types in TME, and sensitivity of chemotherapeutic drugs and immune checkpoint (IC) blockage. The results were validated using digitalized immunohistochemistry and multiplexed immunofluorescence in ESCC tissue samples obtained from our clinical center.
TCGA and validation data suggested that high expression of IDO1 was associated with poor patient survival, and IDO1 was an independent prognostic factor. IDO1 expression positively correlated with macrophages in TME and PDCD1 within diverse IC genes. Single-cell RNA sequencing data analysis and multiplexed immunofluorescence verified the coexpression of IDO1 and PD-1 in tumor-associated macrophages (TAMs). Patients with high IDO1 expression showed increased sensitivity to various chemotherapeutic drugs, while were more likely to resist IC blockage.
This study identifies IDO1 as an independent prognostic indicator of OS in patients with ESCC, reveals a compelling connection of IDO1, PD-1, and TAMs, and explores the sensitivity of patients with high IDO1 expression to chemotherapeutic drugs and their resistance to IC blockade. These findings open new avenues for potential targets in ESCC immunotherapy.
抑制吲哚胺-2,3-双加氧酶1（IDO1）已被提出作为癌症免疫治疗的一种有前景的策略；然而，它在临床试验中失败了。肿瘤微环境（TME）中的巨噬细胞促成免疫逃逸并作为潜在的治疗靶点。本研究调查了IDO1在TME中的表达模式及其对食管鳞状细胞癌（ESCC）患者预后和治疗反应的影响。
使用来自癌症基因组图谱（TCGA）数据库的95例ESCC患者的RNA测序数据来探索IDO1的预后价值。生物信息学工具用于估计肿瘤组织中基质细胞和免疫细胞的评分、TME中八种免疫细胞类型的丰度以及化疗药物和免疫检查点（IC）阻断的敏感性。使用来自我们临床中心的ESCC组织样本中的数字化免疫组织化学和多重免疫荧光对结果进行验证。
TCGA和验证数据表明，IDO1的高表达与患者生存率低相关，并且IDO1是一个独立的预后因素。IDO1表达与TME中的巨噬细胞以及不同IC基因内的程序性细胞死亡蛋白1（PDCD1）呈正相关。单细胞RNA测序数据分析和多重免疫荧光验证了IDO1和程序性死亡受体1（PD-1）在肿瘤相关巨噬细胞（TAM）中的共表达。IDO1高表达的患者对各种化疗药物的敏感性增加，而更有可能抵抗IC阻断。
本研究确定IDO1是ESCC患者总生存期的独立预后指标，揭示了IDO1、PD-1和TAM之间令人信服的联系，并探索了IDO1高表达患者对化疗药物的敏感性及其对IC阻断的抗性。这些发现为ESCC免疫治疗中的潜在靶点开辟了新途径。
