Tumor Long-interspersed Nucleotide Element-1 Methylation Level and Immune Response to Esophageal Cancer

2019 ◽  
Vol 272 (6) ◽  
pp. 1025-1034 ◽  
Author(s):  
Keisuke Kosumi ◽  
Yoshifumi Baba ◽  
Kazuo Okadome ◽  
Taisuke Yagi ◽  
Yuki Kiyozumi ◽  
...  
Keyword(s):  
Immune Response ◽  
Esophageal Cancer ◽  
Methylation Level

PS02.176: LINE-1 METHYLATION LEVEL AND LOCAL IMMUNE RESPONSE IN ESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 172-172
Author(s):  
Yoshifumi Baba ◽  
Taisuke Yagi ◽  
Yuki Kiyozumi ◽  
Yukiharu Hiyoshi ◽  
Masaaki Iwatsuki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Esophageal Cancer ◽  
Methylation Level ◽  
Cpg Island ◽  
Surrogate Marker ◽  
Esophageal Tumor ◽  
Local Immune Response ◽  
Dna Hypomethylation ◽  
Response Status

Abstract Background In cancer cells, DNA methylation may be altered in two principle ways; global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Since Long interspersed element-1 (LINE-1 or L1; a repetitive DNA retrotransposon) constitutes a substantial portion (approximately 17%) of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In previous studies, we demonstrated that LINE-1 hypomethylation was strongly associated with a poor prognosis in esophageal cancer, supporting its potential role as a prognostic marker (Ann Surg 2012). We also found that LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6 (Clin Cancer Res 2014). Given that immunotherapy, as represented by PD-1/PD-L1-targeting antibodies, has increasingly gained attention as a novel treatment strategy for esophageal cancer, better understanding of local immune response status in esophageal cancer is important. The aim of this study is to evaluate the relationship between LINE-1 methylation level and local immune response in esophageal cancer. Methods Using a non-biased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (CD8 expression) by immunohistochemical analysis (Ann Surg 2017). Results TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001). TIL-negative cases demonstrated significantly lower LINE-1 methylation level compared with TIL-positive cases (P = 0.012). This finding certainly supports that LINE-1 methylation level may influence the local immune response status. Conclusion PD-L1 expression was not related with LINE-1 methylation level. Further investigations in this field would provide deeper insights into esophageal tumor immunology and assist the development of new therapeutic strategies against esophageal cancer. Disclosure All authors have declared no conflicts of interest.

The association between smoking and LINE-1 hypomethylation (global DNA hypomethylation) in normal esophageal epithelium of patients with esophageal squamous cell carcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 41-41
Author(s):  
Shiro Iwagami ◽  
Yoshifumi Baba ◽  
Masayuki Watanabe ◽  
Hironobu Shigaki ◽  
Keisuke Miyake ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Squamous Cell ◽  
Methylation Level ◽  
Continuous Variable ◽  
Smoking History ◽  
Esophageal Mucosa ◽  
Esophageal Epithelium ◽  
Dna Hypomethylation

41 Background: DNA methylation is a major epigenetic mechanism in X-chromosome inactivation, imprinting and repression of transposable elements and endogenous retroviral sequences. Global DNA hypomethylation appears to play an important role in genomic instability, leading to cancer development. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. Smoking and alcohol is extremely important as the etiology of esophageal squamous cell carcinoma. Nonetheless, whether or not smoking and alcohol affect LINE-1 methylation level in normal esophageal epithelium of esophageal cancer patients remains uncertain. Methods: We quantified LINE-1 methylation of normal esophageal mucosa using pyrosequencing technology in 118 resected esophageal squamous cell carcinomas. The data on smoking (Brinkman index, absence or presence) and alcohol amount are available in all cases. We excluded preoperatively treated cases. Results: LINE-1 methylation in normal esophageal epithelium of esophageal cancer patients ranged from 57.1 to 92.8 of 0-100 scale (N=118; mean 81.2; median 80.0; standard deviation 7.2). LINE-1 methylation level (continuous variable) was significantly associated with Brickman index (continuous variable) (r=0.12, p=0.0002); heavy smoker had lower LINE-1 methylation level of normal esophageal mucosa. LINE-1 methylation level was lower in patients with smoking history (mean 79.7) than in patients without smoking history (mean 83.2) (p=0.034). Alcohol assumption was not associated with LINE-1 methylation level (r=0.003, p=0.58). Conclusions: Smoking was associated with LINE-1 hypomethylation in esophageal normal epithelium, suggesting the possibility of epigenetic field effects caused by cigarette in esophageal tumorigenesis. Considering that DNA methylation alterations are reversible and can thus be targets for chemoprevention, our findings may have clinical implication.

scholarly journals Abstract 2826: Understanding associations among local microbiome, immune response, and efficacy of immunotherapy in esophageal cancer

2019 ◽  
Author(s):  
Chao Zhang ◽  
Prashant V. Thakkar ◽  
Prateek Sharma ◽  
Sreekar Vennelaganti ◽  
Doron Betel ◽  
...  
Keyword(s):  
Immune Response ◽  
Esophageal Cancer

scholarly journals The Intensity of Radiotherapy-Elicited Immune Response Is Associated with Esophageal Cancer Clearance

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jin-lu Ma ◽  
Long Jin ◽  
Yao-Dong Li ◽  
Chen-chen He ◽  
Xi-jing Guo ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Esophageal Cancer ◽  
Immune Cells ◽  
Interleukin 2 ◽  
Therapeutic Interventions ◽  
Hematologic Toxicity ◽  
Serum Concentrations ◽  
Local Response ◽  
Therapeutic Modalities

Radiation therapy is one of the standard therapeutic modalities for esophageal cancer, achieving its main antitumor efficacy through DNA damage. However, accumulating evidence shows that radiotherapy can substantially alter the tumor microenvironment, particularly with respect to its effects on immune cells. We hypothesized that the immune response elicited by radiotherapy may be as important as the radiation itself for successful treatment. More specifically, immunomodulatory cytokines may enhance the effectiveness of radiotherapy. To investigate this hypothesis, we measured changes in the serum interferon-gamma (IFN-γ) and interleukin-2 (IL-2) concentrations during radiotherapy and compared these modifications with outcomes. We found that serum concentrations of IL-2 and IFN-γwere positively associated with local response to radiotherapy in esophageal cancer. More generally, the intensity of the radiotherapy-elicited immune response was positively associated with local response to radiotherapy in esophageal cancer. Changes in serum IL-2 and IFN-γconcentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin. These results suggest that deciphering the mechanisms of radiotherapy-elicited immune response may help in the development of therapeutic interventions that would enhance the efficacy of radiotherapy and convert some ineffective responses to effective responses.

Analysis of peripheral and local anti-tumor immune response in esophageal cancer patients after NY-ESO-1 protein vaccination

2008 ◽  
Vol 123 (10) ◽  
pp. 2362-2369 ◽  
Author(s):  
Hisashi Wada ◽  
Eiichi Sato ◽  
Akiko Uenaka ◽  
Midori Isobe ◽  
Ryohei Kawabata ◽  
...  
Keyword(s):  
Immune Response ◽  
Esophageal Cancer ◽  
Cancer Patients

Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients

2021 ◽  
Author(s):  
Takeshi Ishikawa ◽  
Shinichi Kageyama ◽  
Yoshihiro Miyahara ◽  
Tetsuya Okayama ◽  
Satoshi Kokura ◽  
...  
Keyword(s):  
Immune Response ◽  
Esophageal Cancer ◽  
Cancer Patients

scholarly journals Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Yao Lu ◽  
Dao Xin ◽  
Lulu Guan ◽  
Mengli Xu ◽  
Yalan Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Esophageal Cancer ◽  
T Cell ◽  
Signaling Pathway ◽  
Squamous Cell ◽  
Antitumor Immune Response ◽  
Cancer Data ◽  
Stat3 Signaling ◽  
Coculture System ◽  
Stat3 Signaling Pathway

PurposeTo characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.MethodsThe Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an in vivo assay, we used a model established with NPIdKO™ mice, which have a reconstituted immune system generated by transplanting PBMCs through intravenous injection, to evaluate the effect of metformin on tumors.ResultsThe TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin via the IL-6/JAK2/STAT3 signaling pathway but was not correlated with the canonical AMPK pathway. In the coculture system, the metformin pretreatment group showed higher T cell activation and better T cell killing function than the control group. Animal experiments confirmed that metformin downregulated PD-L1 expression and that combination treatment with metformin and PD-1 inhibitors synergistically enhanced the antitumor response.ConclusionsMetformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response.

Prognostic significance of LINE-1 methylation level in esophageal squamous cell carcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 26-26 ◽  
Author(s):  
Yoshifumi Baba ◽  
Shiro Iwagami ◽  
Masayuki Watanabe ◽  
Hironobu Shigaki ◽  
Satoshi Ida ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Esophageal Cancer ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Methylation Level ◽  
Prognostic Significance ◽  
Esophageal Mucosa ◽  
Dna Hypomethylation

26 Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. LINE-1 methylation is a useful marker for predicting cancer prognosis and monitoring efficacy of adjuvant therapy. Esophageal squamous cell carcinoma, the major histological type of esophageal cancer in East Asian countries, is one of the most aggressive malignant tumors. Nonetheless, prognostic significance of LINE-1 hypomethylaiton in esophageal cancer remains uncertain. Methods: Using 217 curatively resected esophageal squamous cell carcinomas, we quantified LINE-1 methylation using bisulfite-PCR-pyrosequencing assay. Cox proportional hazards model was used to calculate mortality hazard ratio (HR), adjusted for clinical, epidemiologic, and pathological variables. Results: Esophageal cancers showed significantly lower LINE-1 methylation level compared to matched normal esophageal mucosa (p<0.0001; N=50). Tumoral LINE-1 methylation ranged from 24.8 to 91.8 of 0-100 scale (N=217; mean 64.5; median 65.0; standard deviation 12.8). LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate HR= 2.31, 95% confidence interval (CI) 1.38-3.84, p=0.0017; multivariate HR=1.81, 95% CI 1.06-3.05, p=0.031] and overall survival (log-rank p=0.0013; univariate HR=2.21, 95% CI 1.33-3.60, p=0.0026; multivariate HR=1.87, 95% CI 1.12-3.08, p=0.018]. Conclusions: LINE-1 hypomethylation in esophageal cancer is associated with shorter survival, suggesting its role as a prognostic biomarker. Given that epigenetic changes, including DNA methylation alterations, are reversible and can thus be targets for therapy or chemoprevention, our findings may have considerable clinical implications.

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