HLA-A+ Tertiary Lymphoid Structures with Reactivated Tumor-Infiltrating Lymphocytes Are Associated with a Positive Immunotherapy Response in Esophageal Squamous Cell Carcinoma

Biochemistry Life Sciences Immunology Oncology Medicine Cell Biology
HLA-A+ Tertiary Lymphoid Structures Esophageal Squamous Cell Carcinoma Immunotherapy Tumor-Infiltrating Lymphocytes Antigen Presenting Machinery Gene Expression

In esophageal squamous cell carcinoma (ESCC), immune checkpoint blockade (ICB) therapy has achieved significant clinical benefits. However, the overall response rate to ICB treatment remains low. This study aims to identify biomarkers for ESCC response to ICB therapy and explore their potential clinical relevance.

The authors of the paper come from multiple research institutions, including Fudan University, Zhongshan Hospital, the Chinese Academy of Medical Sciences, and Peking Union Medical College. The findings of this study were published in the 2024 issue of the British Journal of Cancer. The research team includes several members who participated in this study. Zhang Dandan, Jiang Dongxian, and Jiang Liping are co-first authors, while Jia Yuchen, Liu Yun, and Liu Zhihua are corresponding authors.

Research methods included investigating the gene expression of 42 untreated ESCC tumor tissues to identify differentially expressed genes related to various immune therapy responses, tumor-infiltrating lymphocytes, and immune-related gene signatures. The ESCC tumor microenvironment was systematically evaluated using NanoString GeoMx digital spatial profiler, single-cell RNA sequencing, and multiplex immunohistochemistry techniques. Finally, the study assessed the relationship between the HLA-A positive tertiary lymphoid structures (TLS) and the response to ICB among 60 ESCC patients.

The results indicated that among ICB responders, tumor-infiltrating B lymphocytes and several immune-related gene signatures (such as antigen presentation machinery APM markers) were significantly elevated. Multiplex immunohistochemistry identified HLA-A positive TLS, revealing that as TLS matured, the expression of HLA-A by TLS-resident cells gradually increased. Most HLA-A positive cells residing in TLS were tumor-infiltrating T (TIL-T) or B (TIL-B) lymphocytes. Digital spatial analysis and single-cell RNA sequencing of spatially separated TIL-T lymphocytes in 60 ESCC tumor tissues showed that TIL-Ts expressing CXCL13 within TLS are activated by increasing APM marker expression. The study concluded that HLA-A positive TLS and their main cellular components TIL-T and TIL-B are linked to the clinical benefit of ICB treatment in ESCC patients.

The study concluded that HLA-A positive TLS exist in ESCC tumor tissues. TLS-resident TIL-T with elevated APM marker expression may be activated. HLA-A positive TLS and their main cellular components TIL-T and TIL-B may serve as biomarkers for ESCC patients receiving ICB therapy.

This study’s scientific value lies in revealing the importance of tertiary lymphoid structures in the immune response to esophageal squamous cell carcinoma and providing potential predictive biomarkers. The innovation of the research method is in its evaluation of the tumor microenvironment using various advanced immunopathological techniques and a deep exploration of cellular heterogeneity in the tumor microenvironment via single-cell analysis technology. The specificity of the research goal is focused on the function of HLA-A positive TLS in immune checkpoint therapy and its role in the prognosis of esophageal squamous cell carcinoma patients.