Duan Ran, Li Xiaoqin, Zeng Dongqiang, Chen Xiaofeng, Shen Bo, Zhu Dongqin, Zhu Liuqing, Yu Yangyang, Wang Deqiang
Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Department of Ultrasonography, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
Front Immunol. 2021 Jan 25;11:609337. doi: 10.3389/fimmu.2020.609337. eCollection 2020.
Chemotherapy (CT) and radiochemotherapy (RCT) are currently the standard postoperative treatments for resected gastric cancer (GC). However, owing to a lack of predictive biomarkers, their efficacy is currently suboptimal. As tumor microenvironment (TME) has the potential to determine treatment response, we investigated the association of TME status with the efficacy of fluoropyrimidine (FU)-based postoperative CT/RCT in resected GC.
Patients with transcriptome data were screened and selected in three independent cohorts. Favorable (fTME) and poor TME (pTME) were defined by a transcriptome-based TME qualification method. Immune infiltration and hypoxia were assessed.
A total of 535 patients were eligible. fTME, indicating the presence of immune activation, was characterized by NK cell rather than CD8+ T cell infiltration. However, postoperative CT/RCT improved overall survival and disease-free survival time more evidently in patients with pTME GC than those with fTME GC. Stratified by stage in fTME GC, stage III patients benefited from postoperative CT/RCT while stage Ib/II patients did not. In comparison, patients with pTME GC benefited from postoperative CT/RCT, regardless of stage. Furthermore, fTME was more hypoxic than pTME, accompanied by a stronger expression of thymidylate synthase (TS)-the target of FU. Stage Ib/II fTME GC was the most hypoxic and had the strongest TS expression across all the subgroups stratified by TME status and stage.
We found that fTME, with the enrichment of NK cells, may predict the lack of postoperative CT/RCT efficacy in stage Ib/II GC, which may be associated with hypoxia and TS expression. Further validations and mechanism researches are needed.
化疗（CT）和放化疗（RCT）是目前切除术后胃癌（GC）的标准治疗方法。然而，由于缺乏预测性生物标志物，它们的疗效目前并不理想。由于肿瘤微环境（TME）有可能决定治疗反应，我们研究了TME状态与基于氟嘧啶（FU）的术后CT/RCT在切除的GC中的疗效之间的关联。
在三个独立队列中筛选并选择具有转录组数据的患者。通过基于转录组的TME定性方法定义良好的TME（fTME）和不良TME（pTME）。评估免疫浸润和缺氧情况。
共有535例患者符合条件。fTME表明存在免疫激活，其特征是NK细胞浸润而非CD8 + T细胞浸润。然而，与fTME GC患者相比，pTME GC患者术后CT/RCT更明显地改善了总生存期和无病生存期。在fTME GC中按分期分层，III期患者从术后CT/RCT中获益，而Ib/II期患者则未获益。相比之下，pTME GC患者无论分期如何都从术后CT/RCT中获益。此外，fTME比pTME缺氧更严重，同时胸苷酸合成酶（TS）——FU的靶点——表达更强。Ib/II期fTME GC在所有按TME状态和分期分层的亚组中缺氧最严重且TS表达最强。
我们发现，富含NK细胞的fTME可能预示着Ib/II期GC术后CT/RCT疗效不佳，这可能与缺氧和TS表达有关。需要进一步的验证和机制研究。
