Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
Charles Perkins Centre, The University of Sydney, Sydney, Australia.
Histopathology. 2019 May;74(6):817-828. doi: 10.1111/his.13814.
Indoleamine 2,3-dioxygenase (IDO), an immunomodulatory enzyme, facilitates immune escape by tumours and promotes tumour progression. IDO inhibitors with and without additional anti-PD-1 therapy have been evaluated in recent and ongoing melanoma clinical trials, but IDO expression in melanoma tumours, and therefore its potential role as a predictive biomarker remains unknown. This study sought to evaluate IDO expression in immunotherapy-naive metastatic melanoma patients in order to determine patterns of expression in corresponding primary melanomas, locoregional metastases and distant metastases.
Here, we evaluated IDO expression using immunohistochemistry in 99 melanoma tumour samples from 43 immunotherapy-naive patients with metastatic melanoma to determine patterns of expression in primary melanomas (n = 29), locoregional metastases (n = 36) and distant metastases (n = 34). Thirty-seven per cent of patients demonstrated tumour IDO expression in at least one specimen. Twelve of 35 patients (34%) with longitudinal specimens (i.e. two or more separate specimens from different disease stages in the same patient) displayed heterogeneous IDO staining between samples. Tumour IDO expression positively correlated with tumour-infiltrating lymphocyte (TIL) score as well as the number of IDO-expressing mononuclear cells in the primary melanoma (P < 0.0001 and P = 0.0011, respectively) and nodal metastases (P = 0.049 and P = 0.037, respectively), but not in distant metastases. Furthermore, tumour IDO expression correlated positively with PD-L1 expression by melanoma cells among all specimens (P = 0.0073).
Therefore, while assessment of tumour IDO expression warrants evaluation in melanoma patient cohorts treated with IDO inhibitors dosed at levels proven to inhibit the target by pharmacodynamic assessment, its utility as a biomarker may be limited by intertumoral heterogeneity.
色氨酸 2,3-双加氧酶（IDO）是一种免疫调节酶，可促进肿瘤的免疫逃逸并促进肿瘤进展。最近和正在进行的黑色素瘤临床试验评估了具有和不具有额外抗 PD-1 治疗的 IDO 抑制剂，但黑色素瘤肿瘤中的 IDO 表达及其作为预测生物标志物的潜在作用仍然未知。本研究旨在评估免疫治疗初治转移性黑色素瘤患者的 IDO 表达，以确定相应原发性黑色素瘤、局部区域转移和远处转移中表达模式。
在这里，我们使用免疫组织化学法评估了 43 例免疫治疗初治转移性黑色素瘤患者的 99 例黑色素瘤肿瘤样本中的 IDO 表达，以确定原发性黑色素瘤（n=29）、局部区域转移（n=36）和远处转移（n=34）中的表达模式。37%的患者至少有一个标本存在肿瘤 IDO 表达。12 例具有纵向标本（即同一患者不同疾病阶段的两个或多个单独标本）的患者（35%）显示样本之间的 IDO 染色存在异质性。肿瘤 IDO 表达与肿瘤浸润淋巴细胞（TIL）评分以及原发性黑色素瘤（P<0.0001 和 P=0.0011）和淋巴结转移（P=0.049 和 P=0.037）中 IDO 表达的单核细胞数量呈正相关，但与远处转移无关。此外，所有标本中肿瘤 IDO 表达与黑色素瘤细胞中 PD-L1 表达呈正相关（P=0.0073）。
因此，虽然在通过药效学评估证明以抑制目标的剂量用 IDO 抑制剂治疗的黑色素瘤患者队列中评估肿瘤 IDO 表达是合理的，但由于肿瘤间异质性，其作为生物标志物的效用可能有限。
