HLA-A+ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma

Dandan Zhang; Dongxian Jiang; Liping Jiang; Jiakang Ma; Xiaobing Wang; Xingyu Xu; Ziqiang Chen; Mengping Jiang; Wenjing Ye; Jie Wang; Weida Meng; Wenqing Qiu; Yingyong Hou; Jing Huang; Yuchen Jiao; Yun Liu; Zhihua Liu

doi:10.1038/s41416-024-02712-9

HLA-A⁺ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma

Br J Cancer. 2024 May 18. doi: 10.1038/s41416-024-02712-9. Online ahead of print.

Authors

Dandan Zhang^#^{1

2}, Dongxian Jiang^#³, Liping Jiang^#⁴, Jiakang Ma^#^{1

2}, Xiaobing Wang⁴, Xingyu Xu^{1

2}, Ziqiang Chen^{1

2}, Mengping Jiang^{1

2}, Wenjing Ye⁵, Jie Wang⁶, Weida Meng^{1

2}, Wenqing Qiu⁷, Yingyong Hou³, Jing Huang⁸, Yuchen Jiao⁹, Yun Liu^{10

11}, Zhihua Liu¹²

Affiliations

¹ 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.
² State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
³ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
⁵ Division of Rheumatology and Immunology, Huashan Hospital, Fudan University, Shanghai, China.
⁶ Departments of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁷ Shanghai Xuhui Central Hospital, Shanghai, China.
⁸ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁹ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. jiaoyuchen@cicams.ac.cn.
¹⁰ 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. yliu39@fudan.edu.cn.
¹¹ State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China. yliu39@fudan.edu.cn.
¹² State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. liuzh@cicams.ac.cn.

^# Contributed equally.

PMID: 38762674
DOI: 10.1038/s41416-024-02712-9

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Grants and funding

82171837/National Natural Science Foundation of China (National Science Foundation of China)