Department of Thoracic Surgery, Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
Department of abdominal oncology, The cancer center of the fifth affiliated hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Tumori. 2023 Oct;109(5):466-480. doi: 10.1177/03008916231176857. Epub 2023 May 30.
Esophageal squamous cell carcinoma (ESCC) is one of the most common upper gastrointestinal malignancies worldwide. Tertiary lymphoid structures (TLS) are tumor-infiltrating immune cells aggregates coupled with stromal cells which are similar to secondary lymphoid organs. The objective of this study is to explore the predictive effects of two common genes associated with TLS models on prognosis and immunotherapy effects in ESCC patients.
Clinical information for ESCC patients in the TCGA(The Cancer Genome Altas) cohort and GSE 53625 were collected. All of the samples were classified as either high score group or low score group based on two TLS signatures, and the association between TLS signatures and survival, clinical indicators, genomic burden, stemness indices analysis, tumor microenvironment and immunotherapy response were performed. Furthermore, the mature TLS was also assessed in ESCC tissue microarray.
In our study, we quantified the score of TLS_9 and TLS_12, respectively, reflecting the different statuses of TLS (TLS_9 = B and T cells in TLSs; TLS_12 = neogenesis of TLSs). Subsequently, we explored the effect of TLS score on ESCC tumor microenvironment quantified by multiple algorithms. We found that a correlation analysis indicated that TLS_9 and TLS_12 were all positively correlated with CD8+ T cell, NK cells, CD4+ T cells, M1 macrophages and so on. Meanwhile, some cells present a different correlation pattern of TLS_9 and TLS_12, including activated CD4+ memory T cells and Tgd cells. Immune-related analysis revealed that the TLS_12 and TLS_9 scores were all positively correlated with immune dysfunction, yet negatively correlated with immune exclusion. Following this, the biological roles of TLS_9 and TLS_12 scores were investigated. Also, we noticed that the TLS score could significantly affect the CAFs infiltration and be associated with the genomic burden and tumor stemness. In addition, we explored the prognostic value of mature TLS through tissue microarray (TMA). Our result displayed ESCC patients with the presence of mature TLS had a better prognosis than ESCC patients without it.
Our study indicated that ESCC patients with the presence of TLS had better outcomes and an inflamed immune microenvironment. In addition, both TLS-9 and TLS-12 gene signatures could be used as potential biomarkers for the immunotherapy of ESCC patients.
食管鳞状细胞癌（ESCC）是全球最常见的上消化道恶性肿瘤之一。三级淋巴结构（TLS）是与基质细胞耦联的肿瘤浸润免疫细胞聚集物，类似于次级淋巴器官。本研究的目的是探讨与 TLS 模型相关的两种常见基因对 ESCC 患者预后和免疫治疗效果的预测作用。
收集 TCGA（癌症基因组图谱）队列和 GSE53625 中 ESCC 患者的临床信息。根据两个 TLS 特征，将所有样本分为高评分组或低评分组，并对 TLS 特征与生存、临床指标、基因组负担、干性指数分析、肿瘤微环境和免疫治疗反应之间的关系进行了分析。此外，还在 ESCC 组织微阵列中评估了成熟的 TLS。
在本研究中，我们分别量化了 TLS_9 和 TLS_12 的评分，分别反映了 TLS 的不同状态（TLS_9 = TLS 中的 B 细胞和 T 细胞；TLS_12 = TLS 的新生）。随后，我们通过多种算法探讨了 TLS 评分对 ESCC 肿瘤微环境的影响。我们发现，相关性分析表明，TLS_9 和 TLS_12 均与 CD8+T 细胞、NK 细胞、CD4+T 细胞、M1 巨噬细胞等呈正相关。同时，一些细胞呈现出不同的 TLS_9 和 TLS_12 相关模式，包括激活的 CD4+记忆 T 细胞和 Tgd 细胞。免疫相关分析表明，TLS_12 和 TLS_9 评分均与免疫功能障碍呈正相关，与免疫排斥呈负相关。在此基础上，研究了 TLS_9 和 TLS_12 评分的生物学作用。此外，我们还注意到 TLS 评分可显著影响 CAFs 的浸润，并与基因组负担和肿瘤干性有关。另外，我们通过组织微阵列（TMA）探讨了成熟 TLS 的预后价值。结果显示，存在成熟 TLS 的 ESCC 患者的预后优于不存在成熟 TLS 的 ESCC 患者。
本研究表明，存在 TLS 的 ESCC 患者预后较好，且免疫微环境呈炎症状态。此外，TLS-9 和 TLS-12 基因特征均可作为 ESCC 患者免疫治疗的潜在生物标志物。
