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Biology subjects

Hong, M.-H.

Publications and source records attributed to Hong, M.-H..

2 recordsLinked to original sources
bioRxiv2024

Tumor microenvironment distinctions between esophageal cancer subtypes explain varied immunotherapy responses

Esophageal cancer comprises two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous studies have revealed distinct genomic characteristics between these subtypes, with ESCC sharing similarities with head and neck squamous cell carcinoma (HNSCC), and EAC aligning with gastric adenocarcinoma (GAC). Additionally, recent immunotherapy clinical trials have shown a higher response rate in ESCC and HNSCC compared to EAC and GAC. However, how the tumor microenvironment contributes to these varied immunotherapy responses remains unclear. In this study, through a comparative analysis of single-cell tumor transcriptomes from 35 patients with ESCC, EAC, HNSCC, or GAC, we identified two groups with tumor microenvironment distinctions: ESCC and HNSCC versus EAC and GAC, consistent with their genomic classifications. Malignant epithelial cells displayed distinct separations based on histological origin. In the tumor immune microenvironment, we observed an enrichment of CXCL13+CD8+ T cells and CXCL9+CXCL10+ tumor-associated macrophages (TAMs) in ESCC and HNSCC, which activate cellular immunity through interferon-{gamma}. In contrast, EAC and GAC exhibited a high presence of heat-shock protein-expressing CD8+ T cells and MARCO+ TAMs. These immune signatures help explain the varied immunotherapy responses among these cancer subtypes and successfully predict immunotherapy outcomes across diverse cancer types, underscoring their clinical significance.

cancer biology↗
bioRxiv2024

Single-cell multi-omics reveals tumor microenvironment factors underlying poor immunotherapy responses in ALK-positive lung cancer

Anaplastic lymphoma kinase (ALK) rearrangement is a major oncogenic driver in non-small cell lung cancer (NSCLC). While ALK tyrosine kinase inhibitors have shown promising therapeutic effects, overcoming resistance with immunotherapy becomes necessary when resistance develops. However, various clinical trials have revealed that their efficacies remain limited. To investigate the tumor microenvironment (TME) factors contributing to poor immune checkpoint blockade responses in ALK-positive patients, we performed single-cell RNA and ATAC sequencing on lung adenocarcinoma (LUAD) tumors with and without ALK rearrangements. Integrative analysis with additional public LUAD cohorts revealed distinct immune landscapes in ALK-positive tumors, marked by enriched innate immunity and depleted adaptive immunity. ALK-positive malignant cells exhibit higher stemness and aggressive phenotype. Tumor-associated macrophages (TAMs) in these tumors predominantly maintain pro-tumoral M2-like states, reinforcing immune suppression. B cells show reduced immune reactivity and impaired tertiary lymphoid structure formation, while CD8+ T cells display bystander-like signatures and reduced tumor reactivity. Single-cell chromatin accessibility profiles combined with regulatory network analysis suggest that differences in transcription factor activities, rather than chromatin accessibility, may underlie T cell dysfunction. These findings provide insights into the immunosuppressive TME of ALK-positive LUAD, potentially explaining the failure of recent immunotherapy trials and highlighting targets for improving efficacy.

cancer biology↗