MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Shanghai Xuhui Central Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
Br J Cancer. 2024 Jul;131(1):184-195. doi: 10.1038/s41416-024-02712-9. Epub 2024 May 18.
Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance.
We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients.
Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC.
HLA-A TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.
免疫检查点阻断（ICB）疗法为多种癌症类型提供了显著的临床获益。然而，在食管鳞癌（ESCC）中，ICB 治疗的总体反应率仍然较低。本研究旨在确定 ESCC 的 ICB 治疗生物标志物，并探讨其潜在的临床相关性。
我们研究了 42 例未经治疗的 ESCC 肿瘤组织中的基因表达，确定了与免疫治疗反应差异相关的差异表达基因、肿瘤浸润淋巴细胞和免疫相关基因特征。我们使用 NanoString GeoMx 数字空间分析器、单细胞 RNA-seq 和多重免疫组化在 ESCC 中系统地评估了肿瘤微环境。最后，我们在 60 例 ESCC 患者中评估了 HLA-A 阳性三级淋巴结构（TLS）与患者对 ICB 反应之间的关联。
肿瘤浸润 B 淋巴细胞和几种免疫相关基因特征，如抗原呈递机制（APM）特征，在 ICB 治疗反应者中显著升高。多重免疫组化鉴定出 HLA-A TLS 的存在，并表明随着 TLS 的成熟，TLS 驻留细胞越来越多地表达 HLA-A。大多数 TLS 驻留的 HLA-A 细胞是肿瘤浸润 T（TIL-T）或肿瘤浸润 B（TIL-B）淋巴细胞。60 例 ESCC 肿瘤组织的空间差异 TIL-T 淋巴细胞的数字空间分析和单细胞 RNA-seq 数据显示，随着 TLS 的成熟，TLS 内表达 CXCL13 的耗竭 TIL-T 被重新激活，APM 特征的表达水平升高。最后，我们证明了 HLA-A TLS 及其主要细胞成分，TIL-T 和 TIL-B，与 ESCC 的 ICB 治疗临床获益相关。
HLA-A TLS 存在于 ESCC 肿瘤组织中。表达 APM 特征升高的 TLS 驻留 TIL-T 可能被重新激活。HLA-A TLS 及其主要细胞成分，TIL-T 和 TIL-B，可作为 ESCC 患者接受 ICB 治疗的生物标志物。
