Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, China.
Tongji University, No 1239 Siping Road, Shanghai 200433, China.
J Immunother Cancer. 2021 May;9(5). doi: 10.1136/jitc-2021-002339.
Immunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC.
We enrolled 102 patients with histologically confirmed SCLC at stages I-III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts.
In SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and p<0.001). High FOXP3 expression showed longer relapse-free survival (RFS) than the low-level group (41.200 months, 95% CI 26.937 to 55.463, vs 14.000 months, 95% CI 8.133 to 19.867; p=0.008). For tumor-infiltrating lymphocytes (TILs), subgroup analysis demonstrated FOXP3 and PD-1, PD-L1, lymphocyte activation gene-3, CD3, CD4, or CD8 double positive were significantly correlated with longer RFS. We further performed importance evaluation for immune biomarkers, constructed an immune risk score incorporating the top three important biomarkers, FOXP3, TIL PD-L1, and CD8, and found their independently prognostic role to predict SCLC relapse. Better predictive performance was achieved in this immune risk model compared with single-indicator-based or two-indicator-based prediction systems (area under the curve 0.715 vs 0.312-0.711). Then, relapse prediction system integrating clinical staging and immune risk score was established, which performed well in different cohorts. High FOXP3-related genes were enriched in several immune-related pathways, and the close relationships of interleukin-2, , basic excision repair genes , , , and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4 memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC.
FOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.
免疫疗法在一定程度上可能延长小细胞肺癌（SCLC）患者的生存时间。叉头框蛋白 P3（FOXP3）在肿瘤微环境（TME）中的作用仍存在争议。我们旨在研究 FOXP3 相关的表达特征和预后价值，并为 SCLC 开发一种具有临床相关性的预测系统。
我们纳入了 102 名经组织学证实的 I-III 期 SCLC 患者。通过免疫组织化学，我们确定了 FOXP3 的表达模式及其与其他免疫生物标志物的关联。通过机器学习和统计分析，我们构建了有效的免疫风险评分模型。此外，我们在不同队列中检查了 FOXP3 相关的富集途径和 TME 特征。
在 SCLC 中，FOXP3 水平与程序性死亡配体 1（PD-L1）、程序性细胞死亡蛋白 1（PD-1）、CD4、CD8 和 CD3 的状态显著相关（p=0.002、p=0.001、p=0.002、p=0.030 和 p<0.001）。高 FOXP3 表达的患者无复发生存期（RFS）长于低水平组（41.200 个月，95%CI 26.937 至 55.463，vs 14.000 个月，95%CI 8.133 至 19.867；p=0.008）。对于肿瘤浸润淋巴细胞（TIL），亚组分析表明，FOXP3 与 PD-1、PD-L1、淋巴细胞激活基因-3、CD3、CD4 或 CD8 双阳性与 RFS 延长显著相关。我们进一步对免疫生物标志物进行了重要性评估，构建了一个包含三个最重要标志物（FOXP3、TIL PD-L1 和 CD8）的免疫风险评分，并发现它们可以独立预测 SCLC 复发。与基于单一指标或两个指标的预测系统（曲线下面积 0.715 与 0.312-0.711）相比，该免疫风险模型具有更好的预测性能。然后，我们建立了一个整合临床分期和免疫风险评分的复发预测系统，该系统在不同队列中表现良好。高 FOXP3 相关基因在多个免疫相关途径中富集，白细胞介素 2、基础切除修复基因、氧化磷酸化相关基因细胞色素 c 氧化酶亚基 8A 与 FOXP3 表达密切相关。此外，我们发现低免疫风险评分组的激活 CD4 记忆 T 细胞（p=0.014）和浆细胞（p=0.049）数量显著高于高风险组。肿瘤浸润免疫细胞的异质性可能代表 SCLC 风险预测的一个有前途的特征。
FOXP3 与 TME 中肿瘤浸润细胞上的免疫生物标志物密切相关。本研究强调了 FOXP3 在 SCLC 中具有重要的预后价值和有前途的临床应用。
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