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BACKGROUND: Tumor cells (TC) participate in tumor progression by altering the immune responses in the tumor microenvironment. However, the clinical relevance and prognostic effect of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in esophageal squamous cell carcinoma (ESCC) are unknown. The purpose of this study was to investigate the interactions and clinical significance of PD-L1 expression and TILs in ESCC. METHODS: Tissue specimens were collected from 126 patients with ESCC who underwent curative esophagectomy. Immunohistochemical analysis and multiplex immunofluorescence for CD4, CD8, CD25, FOXP3, and PD-L1 in the tumor were used to identify multiple tumor-infiltrating immune cells (TIIC), Tregs, and TC. RESULTS: PD-L1 was expressed in tumor cells (PD-L1 TC). PD-L1 TIIC and PD-L1 TC affected the biological behavior of TC. The positive expression rate of PD-L1 TC and CD8+ TILs was 27.8% (35/126) and 31.7% (40/126), respectively. Kaplan-Meier analysis showed that overall survival (OS) was significantly associated with decreased CD8+ TILs and PD-L1 TC-positive expression, which promote ESCC progression and metastasis. CONCLUSION: Tumor depth, CD8, and PD-L1 TC were independent prognostic factors in ESCC, and a predictive nomogram with these three risk factors improved the accuracy of predicting OS in patients with ESCC after surgical resection. The conjoint analysis of multiple immune-related factors is beneficial for stratifying patient survival risk.

Asunto(s)

Antígeno B7-H1 , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Antígeno B7-H1/metabolismo , Masculino , Femenino , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/inmunología , Pronóstico , Persona de Mediana Edad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/inmunología , Anciano , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/metabolismo , Estimación de Kaplan-Meier , Adulto , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Esofagectomía

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INTRODUCTION: Identifying accurate biomarkers for predicting response to chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC) is a critical challenge. The protein SIRT1, recognized for its implications in longevity, has been associated with tumor promotion in ESCC. However, data regarding its correlation with CRT sensitivity remain unreported. Therefore, in this study, we aimed to investigate the relationship between SIRT1 expression and CRT sensitivity and concurrently assess the effect of SIRT1 knockdown on CRT sensitivity in ESCC. METHODS: This study included 73 patients who underwent radical esophagectomy after CRT. SIRT1 expression in pre-treatment endoscopic biopsies was assessed through immunostaining, followed by a comparative analysis of CRT effects on surgical specimens. Small interfering RNA was used to attenuate SIRT1 expression in TE5 and TE10 cells, which were then subjected to cisplatin treatment at varying doses and concentrations and irradiation with X-rays, respectively. RESULTS: High SIRT1 tissue expression was significantly associated with CRT resistance. Multivariate analysis identified high SIRT1 expression as an independent biomarker for poor CRT response. In TE-5 and TE-10 cells, SIRT1 knockdown significantly decreased cell viability and increased sensitivity to cisplatin and radiation treatment compared to that of the negative control. CONCLUSION: Our study results demonstrate the potential of SIRT1 as a predictive biomarker for CRT response in ESCC, highlighting the heightened sensitivity to CRT upon the transcriptional inactivation of SIRT1. Targeting SIRT1 emerges as a promising strategy for enhancing the efficacy of CRT for ESCC.

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Despite advances in treatment and diagnosis, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains poor. MicroRNAs (miRNAs/miRs) are associated with prognosis in esophageal cancer, indicating that they may help guide treatment decisions. The aim of the present study was to explore exosomal miR-185 as a candidate prognostic biomarker and therapeutic target in ESCC, to investigate its biological function and clinical significance, and to ascertain the applicability of circulating exosomal miR-185 for the development of targeted drugs for ESCC treatment. A GeneChip miRNA array was used to compare exosomal miRNA expression in ESCC cell lines under hypoxia with those under normoxia. Exosomal miR-185 expression was then confirmed by reverse transcription-quantitative PCR. Patient background and prognosis were compared between high and low miR-185 expression groups. Functional analyses were performed to evaluate the antitumor effects of miR-185 in ESCC cells. Global Gene Set Enrichment Analysis of The Cancer Genome Atlas data was also performed, and differentially expressed exosomal miRNAs under hypoxia were identified compared to those under normoxia. Hypoxia markedly decreased the expression of exosomal miR-185 in KYSE-960 and T.Tn cell culture media. Overexpression of miR-185 suppressed the migration, invasion and colony-forming abilities of ESCC lines, and also suppressed cell cycle progression and promoted apoptosis after cisplatin treatment. Notably, high miR-185 expression was associated with signaling pathways related to cell death, DNA damage and p53. Furthermore, circulating exosomal miR-185 levels were associated with cN and cStage, and could predict progression-free survival and disease-specific survival of patients with ESCC after initial treatment. In conclusion, miR-185 holds potential as a prognostic biomarker and therapeutic target in ESCC.

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Small bowel adenocarcinoma (SBA) is a rare tumor with a poor prognosis. Due to its rarity, the research infrastructure for SBA, including cell lines, is inadequate. The present study established a novel SBA cell line, SiCry-15X, using patient-derived xenografts of SBA. The following criteria were defined for establishment: Long-term culturability, tumorigenicity and similarity with the original tumor. The biological characteristics of the cell line, its sensitivity to anticancer drugs and its ability to produce tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were evaluated. SiCry-15X cells adhered and grew as a monolayer, with a population doubling time of 37 h. Polymerase chain reaction results confirmed the human origin of the cell line, and short tandem repeat analysis revealed that the cells were genetically identical to the original tumor. The 50% inhibitory concentrations of 5-fluorouracil, paclitaxel, irinotecan, oxaliplatin and cisplatin for SiCry-15X were 104.05, 0.24, 63.3, 146.55 and 49.29 µM, respectively. CEA and CA19-9 concentrations in the culture media were markedly elevated. In addition, CEA and CA19-9 levels in the serum of cell-derived xenograft model mice were elevated. Moreover, CEA and CA19-9 were produced by SiCry-15X cells and distributed throughout the blood. Furthermore, increases in serum CEA and CA19-9 of cell-derived xenograft model mice were consistent with the clinical course of the disease. The newly established SBA cell line, SiCry-15X, could be an effective tool for conducting further studies on SBA.