Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Br J Cancer. 2021 Feb;124(3):595-603. doi: 10.1038/s41416-020-01138-3. Epub 2020 Oct 26.
The predictive significance of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors remains unclear in gastric cancer (GC) due to the dynamic alteration by treatments. We aimed to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC.
PD-L1 expression was evaluated by multicolour flow cytometry analysis after co-culturing GG cell lines and immune cells with Tmab. IFN-γ in the co-culture experiments was quantified. Immunohistochemistry (IHC) for PD-L1 expression using clinical samples was also performed to confirm PD-L1 alteration by Tmab.
PD-L1 expression was significantly upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells (PBMCs). PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. IFN-γ concentration in conditioned media from co-cultured PBMCs and NK cells with Tmab was significantly higher and anti-IFN-γ significantly suppress the Tmab-induced PD-L1 upregulation. IHC also suggested PD-L1 upregulation after Tmab treatment.
Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of the predictive significance of PD-L1 expression for PD-1 inhibitors.
由于治疗的动态改变，程序性死亡配体 1（PD-L1）对程序性死亡 1（PD-1）抑制剂在胃癌（GC）中的预测意义尚不清楚。我们旨在阐明曲妥珠单抗（Tmab）对 GC 中 PD-L1 表达的影响。
通过 Tmab 与 GG 细胞系和免疫细胞共培养后进行多色流式细胞术分析评估 PD-L1 表达。共培养实验中定量 IFN-γ。还使用临床样本进行 PD-L1 表达的免疫组织化学（IHC），以确认 Tmab 对 PD-L1 的改变。
在与外周血单核细胞（PBMCs）共培养的 HER2 扩增 GC 细胞系中，TMab 显著上调 PD-L1 表达。TMab 还以时间依赖性方式在与 NK 细胞共培养的 GC 细胞中观察到 PD-L1 上调，但与单核细胞共培养时则没有。与 PBMCs 和 NK 细胞共培养的条件培养基中 IFN-γ浓度显着升高，抗 IFN-γ显着抑制 Tmab 诱导的 PD-L1 上调。IHC 还提示 Tmab 治疗后 PD-L1 上调。
TMab 可以通过与 NK 细胞相互作用上调 GC 细胞上的 PD-L1 表达。这些结果提示在评估 PD-L1 表达对 PD-1 抑制剂的预测意义方面具有临床意义。
