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Impacts of Cigarette Smoking on the Tumor Immune Microenvironment in Esophageal Squamous Cell Carcinoma.

ABSTRACT: Objective: Cigarette smoking is a carcinogenic factor for esophageal cancer and evidence also indicates its effects on tumor microenvironment in patients with esophageal squamous cell carcinoma (ESCC). Materials and Methods: In our study, we demonstrated nine immune infiltrating cells and markers in non-smokers and smokers of 189 non-drinking ESCC patients with multiplex fluorescent immunohistochemistry (mflHC) staining and multispectral imaging. The impacts of cigarette smoking on tumor microenvironment and patient prognosis were also analyzed. Results: Among 189 ESCC patients of non-drinker, 86 patients was current smokers, while 34 males and 59 females were non-smokers and 10 former-smokers. Among 34 male non-smokers and 83 smokers, distinct immune infiltrating cells, with increased DCs in stromal regions (P=0.033), elevated infiltration of Treg cells in intraepithelial regions (P=0.010) and reduced activate cytotoxic T lymphocytes (aCTLs) in both intraepithelial (P=0.021) and stromal regions (P=0.017), were observed in tumor specimens of smoking males, implying an immune suppressed response during cigarette smoke exposure. For smoking characters, the level of stromal tumor-associated macrophages (TAMs) infiltration was correlated with smoking year after age adjusted (r_s =0.352, P=0.002). Though cigarette smoking did not alter the expression of programmed death ligand 1 (PD-L1) in epithelial cells or TAMs in tumor specimens, higher expression of PD-L1 predicted a worse survival in non-smokers but not smokers. Conclusions: Our findings indicated smoking may impair T cell-mediated immune response and supported the possible impacts of cigarette smoking in PD-L1 related research and therapy of ESCC.

SUBMITTER: Wang G

PROVIDER: S-EPMC8771511 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background Esophageal cancer (EC) is a highly aggressive malignancy that is classified as esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Infiltrating stromal/immune cells, a major component of the tumor immune microenvironment (TIME), have prognostic significance in various cancers. Methods In this study we investigated genes and immune factors in the tumor microenvironment (TME) of ESCC and EAC that can serve as prognostic biomarkers. Stromal and immune scores were calculated using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) algorithm based on gene expression profiles of patient-derived tumor tissues in The Cancer Genome Atlas database. The correlation between ESTIMATE scores and survival rates in EC were analyzed. A comparison of high and low stromal/immune score groups revealed multiple differentially expressed genes (DEGs) as candidate prognostic genes; their role in immune-related biological processes was evaluated by functional and protein-protein interaction (PPI) network analyses, and the genes were validated using Gene Expression Omnibus datasets. Additionally, 22 tumor-infiltrating immune cell (TIIC) subsets were analyzed using the CIBERSORT algorithm. Results Median stromal score was higher whereas immune score was lower in ESCC than in EAC (both P<0.01). Stromal score was lower in female as compared to male ESCC patients (P<0.05), and was significantly correlated with T stage (P<0.05). In EAC, median immune score was higher in female as compared to male patients (P<0.05) and was correlated with tumor-node-metastasis stage (P<0.05). The identified DEGs were mainly involved in lymphocyte (especially T-lymphocyte) activation and carbohydrate binding. Moreover, the levels of infiltrating resting-stage dendritic cells, CD8+ T cells, naïve B cells, activated mast cells, and resting memory CD4+ T cells were significantly correlated with EC prognosis (P<0.05). Conclusions The immune microenvironment of ESCC and EAC are quite different. We have found genes with prognostic value in multiple tumor databases.

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Impacts of Cigarette Smoking on the Tumor Immune Microenvironment in Esophageal Squamous Cell Carcinoma.

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