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

May 18, 2024British journal of cancer

Immune cell clusters with active tumor-fighting cells linked to better immunotherapy response in esophageal cancer

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Abstract

HLA-A-positive tertiary lymphoid structures (TLSs) are present in esophageal squamous cell carcinoma (ESCC) tumor tissues.

Tumor-infiltrating B lymphocytes and several immune-related gene signatures are significantly higher in patients who respond to immune checkpoint blockade therapy.
HLA-A expression increases in TLS-resident cells as these structures mature.
Most HLA-A-positive cells in TLSs are tumor-infiltrating T or B lymphocytes.
Exhausted tumor-infiltrating T lymphocytes expressing CXCL13 may be reactivated with increased APM signature expression as TLSs mature.
HLA-A-positive TLSs and their associated T and B lymphocytes may serve as potential biomarkers for predicting clinical benefit from immune checkpoint blockade in ESCC.

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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-ATLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-Acells 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-ATLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. + + +

CONCLUSIONS: HLA-ATLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-ATLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients. + +

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

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