Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Cancer Sci. 2022 Mar;113(3):852-863. doi: 10.1111/cas.15253. Epub 2022 Jan 14.
The limited response rate of immunotherapy in upper tract urothelial carcinoma (UTUC) might be attributed to additional immunosuppressive mechanisms in vivo. As a promising immune checkpoint target, the expression and prognostic role of indoleamine 2,3-dioxygenase 1 (IDO1) in UTUC remains unknown. In this study, the expression and prognostic value of IDO1 was analyzed in 251 patients from 3 independent cohorts. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to construct an IDO1-based immune classifier and external validation was performed to further validate the classifier. RNA sequencing and immunofluorescence were used to explore the immune contexture of different risk groups stratified by classifier. We found that high IDO1 expression on tumor cells (TC) indicated a poorer overall survival and disease-free survival in all cohorts. Patients with high expression of IDO1 TC possessed increased infiltration of CD4 , CD8 and Foxp3 T cells. An immune classifier based on intratumoral CD8 lymphocytes, IDO1 TC, and stromal PD-L1 expression status was developed, with its area under the curves (AUCs) values for overall survival at 5 y being 0.79 (95% confidence interval [CI] 0.65-0.93) in the discovery cohort, 0.75 (95% CI 0.58-0.92) and 0.78 (95% CI 0.65-0.92) in the internal and external validation cohorts, respectively. The high-risk group stratified by the immune classifier was associated with immunosuppressive contexture, accompanied by enhanced CD8 T cells exhaustion patterns. Our IDO1-based immune classifier can provide a superior accuracy for survival prediction and lead to individual stratification of UTUC immune subtypes.
免疫疗法在上尿路尿路上皮癌（UTUC）中的有限反应率可能归因于体内额外的免疫抑制机制。作为一种有前途的免疫检查点靶标，吲哚胺 2,3-双加氧酶 1（IDO1）在上尿路尿路上皮癌中的表达和预后作用尚不清楚。在这项研究中，分析了来自 3 个独立队列的 251 名患者的 IDO1 表达和预后价值。使用最小绝对收缩和选择算子（LASSO）Cox 回归模型构建了基于 IDO1 的免疫分类器，并进行了外部验证以进一步验证该分类器。RNA 测序和免疫荧光用于探索基于分类器分层的不同风险组的免疫结构。我们发现肿瘤细胞（TC）上高 IDO1 表达与所有队列中的总生存率和无病生存率较差相关。IDO1 TC 高表达的患者具有更多浸润的 CD4 、CD8 和 Foxp3 T 细胞。基于肿瘤内 CD8 淋巴细胞、IDO1 TC 和基质 PD-L1 表达状态的免疫分类器被开发出来，其在发现队列中的 5 年总生存率的曲线下面积（AUC）值为 0.79（95%置信区间[CI]0.65-0.93），内部和外部验证队列分别为 0.75（95%CI0.58-0.92）和 0.78（95%CI0.65-0.92）。基于免疫分类器分层的高危组与免疫抑制结构有关，同时伴有增强的 CD8 T 细胞衰竭模式。我们的基于 IDO1 的免疫分类器可为生存预测提供更高的准确性，并导致 UTUC 免疫亚型的个体化分层。
