Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Anatomía Patológica, Clínica Alemana- Facultad de Medicina Universidad del Desarrollo, Vitacura, Santiago, Chile.
J Immunother Cancer. 2017 Oct 17;5(1):81. doi: 10.1186/s40425-017-0285-7.
Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC).
IDO1 protein was measured using quantitative immunofluorescence in 362 stage I-III HR+ BC represented in tissue microarrays. IDO1 levels were determined in the tumor and stroma, and stratified using median cut-point. Associations between IDO1, clinico-pathological features and CD3+, CD8+, CD20+ and FOXP3 tumor-infiltrating lymphocytes were examined using χ and Mann-Whitney tests. Survival was studied using Kaplan-Meier estimator and a proportional hazards model. All tests were two-sided.
IDO1 protein was observed in 76.2% of HR+ BC. There was no association between IDO1 and major clinico-pathological characteristics. Increased IDO1 correlated with decreased CD20+ infiltration (P = 0.0004) but not with CD3+, CD8+ or FOXP3 levels. Elevated IDO1 expression was associated with worse 20-year overall survival (log-rank P = 0.02, HR = 1.39, 95% C.I.: 1.05-1.82). IDO1 scores were independently associated with outcome in multivariable analysis.
IDO1 protein is expressed in the majority of HR+ BC and is an independent negative prognostic marker. Additionally, IDO1 expression is negatively associated with tumor B-cell infiltration. Measurement of IDO1 has the potential to identify a population that might derive benefit from IDO1 blockade.
针对免疫抑制途径的免疫刺激疗法可在晚期实体瘤中产生持久的反应。吲哚胺 2,3-双加氧酶 (IDO) 是限速氧化还原酶，可催化色氨酸降解为犬尿氨酸。IDO 通过下调 CD8+和效应 CD4+T 细胞反应诱导免疫耐受。IDO1 是最活跃的同工酶，在多种肿瘤类型中表达，可使用小分子抑制剂进行靶向治疗。我们使用客观的原位测定法测量了激素受体阳性乳腺癌 (HR+BC) 中 IDO1 的表达。
使用组织微阵列中的 362 例 I-III 期 HR+BC 的定量免疫荧光法测量 IDO1 蛋白。在肿瘤和基质中确定 IDO1 水平，并使用中位数切割点进行分层。使用 χ 和曼-惠特尼检验检查 IDO1 与临床病理特征以及 CD3+、CD8+、CD20+和 FOXP3 肿瘤浸润淋巴细胞之间的关系。使用 Kaplan-Meier 估计器和比例风险模型研究生存情况。所有检验均为双侧检验。
在 76.2%的 HR+BC 中观察到 IDO1 蛋白。IDO1 与主要临床病理特征之间无相关性。IDO1 增加与 CD20+浸润减少相关（P=0.0004），但与 CD3+、CD8+或 FOXP3 水平无关。高水平的 IDO1 表达与 20 年总生存率降低相关（对数秩检验 P=0.02，HR=1.39，95%CI：1.05-1.82）。IDO1 评分在多变量分析中与结局独立相关。
IDO1 蛋白在大多数 HR+BC 中表达，是独立的预后不良标志物。此外，IDO1 表达与肿瘤 B 细胞浸润呈负相关。IDO1 的测量有可能识别出可能受益于 IDO1 阻断的人群。
