PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes
PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes
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DOI：
10.1038/modpathol.2016.95
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发表时间：
2016-09-01
期刊：
影响因子：
7.5
通讯作者：
Mino-Kenudson, Mari
中科院分区：
文献类型：
--
作者：
Rosenbaum, Matthew W.;Bledsoe, Jacob R.;Mino-Kenudson, Mari
程序性细胞死亡1（PD-1）及其配体（PD-L1）是细胞毒性免疫应答的关键抑制因子。肿瘤细胞上的PD-L1表达可能由免疫微环境诱导，导致免疫逃逸（适应性免疫抵抗），以及许多恶性肿瘤的不良预后。在结直肠癌中，对PD-1/PD-L1抑制的反应与微卫星不稳定性相关。然而，对PD-L1表达的结直肠癌的临床病理学、分子生物学和预后特征知之甚少。我们对181例已知微卫星不稳定性和突变状态的结直肠癌患者进行了PD-L1免疫组化，并将PD-L1表达与临床病理特征（包括肿瘤浸润淋巴细胞负荷/免疫表型、肿瘤突变特征和疾病特异性生存率）相关联。PD-L1在16例患者（9%）的肿瘤中表达，这些患者通常年龄较大（P = 0.006）和女性（P = 0.035），肿瘤大小较大（P = 0.013），但分期较低（P < 0.001）。PD-L1表达与CD 8和TBET阳性肿瘤浸润淋巴细胞增加、髓样表型、分化差、微卫星不稳定性、BRAF突变（各P < 0.001）和KRAS突变频率降低（P = 0.012）相关。在多变量分析中，PD-L1表达与髓质形态学和频繁的CD 8阳性肿瘤浸润淋巴细胞相关，表明获得性免疫抵抗。PD-L1阳性并不能预测整个队列的生存率，但它与微卫星不稳定性高队列中较低的疾病特异性生存率相关。PD-L1在结直肠癌中的表达与结直肠癌发生的锯齿状途径的临床病理学和分子特征相关，并且与微卫星不稳定肿瘤的预后较差相关。这些发现支持PD-L1表达在为正常免疫原性结直肠癌提供免疫逃避手段和更具侵袭性的生物学方面的作用，为微卫星不稳定结直肠癌对PD-1/PD-L1通路阻断的有利反应提供了潜在的机制解释，并表明PD-L1免疫组织化学在结直肠癌中的潜在预测和预后作用。
Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P = 0.006) and female (P = 0.035), with tumors exhibiting a larger size (P = 0.013), but lower stage ( P < 0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (P < 0.001 for each), and a lower frequency of KRAS mutation (P = 0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma.