Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Mod Pathol. 2019 Apr;32(4):511-523. doi: 10.1038/s41379-018-0160-1. Epub 2018 Oct 26.
Like programmed cell death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well studied in lung adenocarcinoma. PD-L1 and IDO1 expression was evaluated in 261 resected lung adenocarcinomas using tissue microarrays and H-scores (cutoff: 5). We compared IDO1 and PD-L1 expression with clinical features, tumor-infiltrating lymphocytes, HLA class I molecule expression, molecular alterations, and patient outcomes. There was expression of PD-L1 in 89 (34%) and IDO1 in 74 (29%) cases, with co-expression in 49 (19%). Both PD-L1 and IDO1 were significantly associated with smoking, aggressive pathologic features, and abundant CD8+ and T-bet+ (Th1 marker) tumor-infiltrating lymphocytes. PD-L1 expression was also associated with preserved HLA class I molecule expression (p = 0.002). Compared to PD-L1+/IDO1+ and PD-L1+ only cases, significantly fewer IDO1+ only cases had abundant CD8+ and T-bet+ tumor-infiltrating lymphocytes (p < 0.001, respectively). PD-L1 expression was significantly associated with EGFR wild-type (p < 0.001) and KRAS mutants (p = 0.021), whereas isolated IDO1 expression was significantly associated with EGFR mutations (p = 0.007). As for survival, PD-L1 was a significant predictor of decreased progression-free and overall survival by univariate but not multivariate analysis, while IDO1 was not associated with progression-free or overall survival. Interestingly, there was a significant difference in the 5-year progression-free and overall survival (p = 0.004 and 0.038, respectively), where cases without PD-L1 or IDO1 expression had the longest survival, and those with PD-L1 alone had the shortest survival. While PD-L1+/-IDO1 expression is observed in association with HLA class I expression, cytotoxic T lymphocyte/Th1 microenvironments, EGFR wild-type, and KRAS mutations, isolated IDO1 expression does not demonstrate these associations, suggesting that IDO1 may serve a distinct immunosuppressive role in lung adenocarcinomas. Thus, further investigation of IDO1 may demonstrate its role as a potential biomarker for patients who undergo anti-PD-1/PD-L1 therapy.
与程序性细胞死亡配体 1（PD-L1）一样，吲哚胺 2,3-双加氧酶 1（IDO1）已知具有免疫抑制作用，并在人类肺癌中呈不同程度表达。然而，IDO1 的表达在肺腺癌中尚未得到很好的研究。我们使用组织微阵列和 H 评分（截点：5）评估了 261 例切除的肺腺癌中的 PD-L1 和 IDO1 表达。我们将 IDO1 和 PD-L1 的表达与临床特征、肿瘤浸润淋巴细胞、HLA Ⅰ类分子表达、分子改变以及患者结局进行了比较。89 例（34%）存在 PD-L1 表达，74 例（29%）存在 IDO1 表达，49 例（19%）存在共表达。PD-L1 和 IDO1 均与吸烟、侵袭性病理特征以及丰富的 CD8+和 T-bet+（Th1 标志物）肿瘤浸润淋巴细胞显著相关。PD-L1 表达也与保留的 HLA Ⅰ类分子表达相关（p=0.002）。与 PD-L1+/IDO1+和 PD-L1+仅病例相比，IDO1+仅病例的 CD8+和 T-bet+肿瘤浸润淋巴细胞明显较少（分别为 p<0.001）。PD-L1 表达与 EGFR 野生型显著相关（p<0.001）和 KRAS 突变型（p=0.021），而单独的 IDO1 表达与 EGFR 突变型显著相关（p=0.007）。至于生存，PD-L1 是无进展生存期和总生存期的显著预测因子，单因素分析而非多因素分析，而 IDO1 与无进展生存期或总生存期无关。有趣的是，无 PD-L1 或 IDO1 表达的病例 5 年无进展和总生存率有显著差异（p=0.004 和 0.038），其中最长的生存率，而 PD-L1 单阳性病例的生存率最短。虽然 PD-L1+/-IDO1 表达与 HLA Ⅰ类表达、细胞毒性 T 淋巴细胞/Th1 微环境、EGFR 野生型和 KRAS 突变相关，但单独的 IDO1 表达并不显示这些相关性，表明 IDO1 在肺腺癌中可能具有不同的免疫抑制作用。因此，进一步研究 IDO1 可能显示其作为接受抗 PD-1/PD-L1 治疗的患者潜在生物标志物的作用。
