PLEK2 和 IFI6，代表间充质和免疫抑制的微环境，预测食管鳞癌对新辅助免疫治疗的耐药性。
PLEK2 and IFI6, representing mesenchymal and immune-suppressive microenvironment, predicts resistance to neoadjuvant immunotherapy in esophageal squamous cell carcinoma.
机构信息
The Second School of Clinical Medicine, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, China.
Department of Oncology, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.123 Huifu Road West, Guangzhou, 510180, China.
出版信息
Cancer Immunol Immunother. 2023 Apr;72(4):881-893. doi: 10.1007/s00262-022-03288-0. Epub 2022 Sep 19.
BACKGROUND
Immunotherapy has largely improved clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). However, a proportion of patients still fail to benefit. Thus, biomarkers predicting therapeutic resistance and underlying mechanism needs to be investigated.
METHODS
Transcriptomic profiling was applied in FFPE tissues from 103 ESCC patients, including surgical samples from 66 treatment-naïve patients with long-term follow-up, and endoscopic biopsies from 37 local advanced ESCC cases receiving neoadjuvant immunotherapy plus chemotherapy. Unsupervised clustering indicated an aggressive phenotype with mesenchymal character in 66 treatment-naïve samples. Univariant logistic regression was applied to identify candidate biomarkers potentially predicted resistance to neoadjuvant immunotherapy within the range of mesenchymal phenotype enriched genes. These biomarkers were further validated by immunohistochemistry. Putative mechanisms mediating immunotherapy resistance, as indicated by microenvironment and immune cell infiltration, were evaluated by transcriptomic data, and validated by multiplex immunofluorescence.
RESULTS
PLEK2 and IFI6, highly expressed in mesenchymal phenotype, were identified as novel biomarkers relating to non-MPR in neoadjuvant immunotherapy cohort [PLEK2, OR (95% CI): 2.15 (1.07-4.33), P = 0.032; IFI6, OR (95% CI): 2.21 (1.16-4.23), P = 0.016). PLEK2 and IFI6 ESCC patients (versus low expressed patients) further exhibit higher chance of non-major pathological remissions (90%, P = 0.004) in neoadjuvant immunotherapy cohort and high mortality (78.9%, P = 0.05), poor prognosis in retrospective cohort. PLEK2/IFI6 ESCC recapitulated mesenchymal phenotype, characterized by extracellular matrix composition and matrix remodeling. In addition, PLEK2 or IFI6 ESCC displayed an immune-unfavored microenvironment, represented by positive correlating with regulatory T cells, Helper 2 T cell as well as less infiltration of B cells, effector T cells and mast cells.
CONCLUSIONS
PLEK2 and IFI6 was discovered of first time to identify a distinct ESCC subpopulation cannot be benefited from neoadjuvant immunotherapy and present a poor survival, which putatively associated with mesenchymal and immune-suppressive microenvironment.
背景
免疫疗法已在很大程度上改善了食管鳞癌（ESCC）患者的临床预后。然而，仍有一部分患者无法从中获益。因此，需要寻找预测治疗抵抗的生物标志物，并探讨其潜在的作用机制。
方法
采用转录组学方法分析了 103 例 ESCC 患者的 FFPE 组织标本，包括 66 例未经治疗且随访时间较长的初治患者的手术标本和 37 例接受新辅助免疫联合化疗的局部晚期 ESCC 患者的内镜活检标本。非监督聚类分析显示，66 例初治样本中存在一种具有间质特征的侵袭性表型。采用单变量逻辑回归分析确定了间质表型富集基因范围内可能预测新辅助免疫治疗抵抗的候选生物标志物。采用免疫组织化学法进一步验证这些生物标志物。通过转录组数据评估了介导免疫治疗抵抗的潜在机制，包括微环境和免疫细胞浸润，并通过多重免疫荧光进行了验证。
结果
在新辅助免疫治疗队列中，高表达于间质表型的 PLEK2 和 IFI6 被鉴定为与非主要病理缓解（MPR）相关的新型生物标志物[PLEK2，OR（95%CI）：2.15（1.07-4.33），P=0.032；IFI6，OR（95%CI）：2.21（1.16-4.23），P=0.016]。与低表达患者相比，PLEK2 和 IFI6 高表达的 ESCC 患者在新辅助免疫治疗队列中更有可能出现非主要病理缓解（90%，P=0.004），在回顾性队列中具有更高的死亡率（78.9%，P=0.05）和预后不良。PLEK2/IFI6 ESCC 重现了间质表型，其特征为细胞外基质组成和基质重塑。此外，PLEK2 或 IFI6 ESCC 表现出免疫不利的微环境，表现为与调节性 T 细胞、辅助性 2 T 细胞呈正相关，以及 B 细胞、效应 T 细胞和肥大细胞浸润减少。
结论
首次发现 PLEK2 和 IFI6 可识别不能从新辅助免疫治疗中获益的 ESCC 亚群，并提示其预后不良，这可能与间质和免疫抑制性微环境有关。
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