Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.
Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.
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DOI：
10.1136/gutjnl-2015-310839
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发表时间：
2017-05
期刊：
影响因子：
24.5
通讯作者：
Kelly RJ
中科院分区：
文献类型：
--
作者：
Thompson ED;Zahurak M;Murphy A;Cornish T;Cuka N;Abdelfatah E;Yang S;Duncan M;Ahuja N;Taube JM;Anders RA;Kelly RJ
最近的数据支持免疫检查点抑制剂在实体瘤治疗中的重要作用。在这里，我们评估胃和胃食管交界处（G/GEJ）腺癌的程序性死亡配体1（PD-L1）的表达，CD 8 + T细胞的浸润以及这两个因素与患者生存的关系。对34例原发性浸润性G/GEJ切除标本进行PD-L1和CD 8免疫组化染色，并进行EB病毒（EBV）DNA原位杂交。使用全载玻片数字成像分析肿瘤内和肿瘤-基质界面处的CD 8 + T细胞密度。根据PD-L1状态和CD 8密度评价患者生存期。12%的切除显示肿瘤细胞膜PD-L1表达，44%显示免疫基质内表达。2例（6%）EBV阳性，1例显示膜PD-L1阳性。肿瘤和免疫间质内CD 8+密度的增加与肿瘤（p=0.027）和间质（p=0.005）PD-L1表达百分比的增加相关。肿瘤和免疫间质PD-L1表达以及高肿瘤内或间质CD 8 + T细胞密度（>500/mm 2）均与无进展生存期（PFS）和总生存期（OS）较差相关。PD-L1在G/GEJ的所有阶段和组织学中均在肿瘤细胞和免疫基质中表达。令人惊讶的是，我们证明了增加的CD 8浸润与PFS和OS受损相关。具有较高CD 8 + T细胞密度的患者也具有较高的PD-L1表达，表明可能发生了适应性免疫抵抗机制。G/GEJ免疫微环境的进一步表征可以突出基于免疫的治疗的靶点。
Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastrooesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein–Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour–stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.