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Comparative single-cell analysis of esophageal cancer subtypes reveals cellular distinctions explaining varied immunotherapy responses

ABSTRACT: Esophageal cancer comprises two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous studies revealed their distinct genomic characteristics, sharing similarities with head and neck squamous cell carcinoma (HNSCC) and gastric adenocarcinoma (GAC) for ESCC and EAC, respectively. This study compares ESCC and EAC at single-cell resolution to identify factors explaining differences in immunotherapy response rates. We performed comparative single-cell transcriptome analysis for four cancer types near the esophagus using data from 35 patients with ESCC, EAC, HNSCC, or GAC. Malignant epithelial cells showed distinct separations between subtypes based on histological origins. We identified enrichment of CXCL13+ CD8+ T cells and CXCL9+CXCL10+ TAMs in ESCC and HNSCC, promoting a hot-tumor environment through interferon-γ pathways. Conversely, hypoxia and cold-tumor related populations, such as heat-shock protein high CD8+ T cells and MARCO+ TAMs, were enriched in EAC and GAC. These immune subsets' expression signatures predicted immunotherapy responses across diverse cancer types.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273127 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Esophageal cancers (ECs) are highly aggressive tumors with poor prognosis and few treatment options. This study investigated the possibility of treating esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells by inhibitors of broad and specific histone deacetylases (HDACi; SAHA, MS-275, FK228) and/or of DNMT (Azacytidine, AZA). Drug targets (HDAC1,2,3 and DNMT1) were present in non-neoplastic (HET-1A), ESCC (OE21) and EAC (OE33) cell lines. All cell lines responded to HDACi by reduced HDAC activity and increased histone acetylation as well as to AZA by up-regulation of p21. Expression of drug targets remained largely unaffected by HDACi and AZA treatment. Importantly, cell viability, apoptosis, cell cycle dynamics and DNA damage were only affected by HDACi and/or AZA in ESCC and EAC, but not the non-neoplastic cells. This was specifically seen for the combination of MS-275 and AZA, leading to enhanced cancer cell selectivity and drug efficiency. By transcriptome analyses of MS-275, AZA and MS-275/AZA treated cells, known (e.g. p21) as well as novel regulated genes significantly associated with the cellular effects post HDACi and/or AZA treatment in ESCC and EAC cells were identified. Finally, human EC tissue specimens frequently expressed the actionable drug targets HDAC1/2/3 and DNMT1. In summary, a combined HDACi (MS-275)/AZA treatment is cancer cell selective and efficient in vitro. Since the majority of ECs express the drug targets in situ, this paves the way for further investigations of HDACi/AZA treatment in esophageal cancer cells and their translation into a clinico-pathological setting. To elucidate the transcriptome response to HDAC inhibitors of normal esophageal cells and esophageal tumor cells, total RNA was isolated from non-neoplastic esophageal epithelial cells (Het1A cells) a well as from two esophageal tumor cell lines (OE21 and OE33), respectively. Cells were treated with either MS-275, Azacytidine (AZA) or in combination of both. DMSO treatment was used as control in each case. Total RNA was isolated from cells 24 h after treatment and experiments were performed in biological triplicates.

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Comparative single-cell analysis of esophageal cancer subtypes reveals cellular distinctions explaining varied immunotherapy responses

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