BACKGROUND
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined.
METHODS
Summary-level genome-wide association study (GWAS) data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran's Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in esophagogastric junction (EGJ) organoids and mouse models.
RESULTS
MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4 + T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR + T-cell axis, experimental studies demonstrated that FGF19 promotes EGJ glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8 + T cells, validated in EGJ organoids and mouse models.
CONCLUSIONS
This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a candidate cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8 + T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
Yixin Liu, Zhipeng Gong, Yuwen Tan et al.· Journal of Translational Med...· 0 citations
Neoadjuvant immunochemotherapy (nICT) has emerged as a promising neoadjuvant strategy for esophageal squamous cell carcinoma (ESCC). Identification of the factors affecting the responsiveness to nICT could help further improve treatment efficacy. Here, we performed single-cell analysis on 14 ESCC patients undergoing nICT and revealed tumor microenvironment (TME) features associated with differential treatment responses. Nonnegative matrix factorization (NMF) identified five coordinated cellular programs with distinct response associations. Specifically, the NMF3 program mainly comprising immunosuppressive cell subsets was enriched in the minimal or no pathological tumor regression (TRS3) group, in which regulatory T cells (Tregs) and dendritic cells (DCs) exhibited close correlation. In addition, elevated expression of mitochondrial transcription factor A (TFAM) in DCs was associated with increased Treg infiltration in the TRS3 group. A myeloid-specific Tfam knockout mouse model showed that TFAM deficiency reversed the immunosuppressive TME, inhibited tumor growth, and enhanced response to anti-PD-1 therapy in ESCC. Mechanistically, TFAM deficiency in DCs activated the STING-TBK1-IRF3 pathway, thereby promoting DC maturation to enhance anti-tumor immunity. Overall, this study characterized the TME in residual ESCC after nICT and revealed an association between elevated TFAM expression in DCs and poor responsiveness to nICT. These findings indicate the critical role of TFAM deficiency in DCs in activating anti-tumor immunity, highlighting the potential of targeting TFAM to improve the efficacy of immunotherapy and optimize therapeutic strategies.
Linyan Chen, Tang Feng, Jianfeng Zhou et al.· Cancer Research· 1 citation
FGF19 emerges as a key cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8+ T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
Yixin Liu, Jianfeng Zhou, Yushang Yang et al.· Diseases of the esophagus· 0 citations
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