Impact of the inflammatory microenvironment on T-cell phenotype in the progression from reflux oesophagitis to Barrett oesophagus and oesophageal adenocarcinoma

Kavanagh, Maria E.; Conroy, Melissa J.; Clarke, Niamh; Gilmartin, Niamh T.; O’Sullivan, Katie E.; Feighery, Ronan; MacCarthy, F; O’Toole, Dermot; Ravi, Narayanasamy; Reynolds, John V.; O’Sullivan, Jacintha; Lysaght, Joanne

doi:10.1016/j.canlet.2015.10.019

Cited by 48 publications

(49 citation statements)

References 28 publications

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“…Our immune marker profiling overall suggested an activation of pro-tumor immune pathways (i.e., Th2) and B-cell receptor signaling as well as an inhibition of anti-tumor immune response (e.g., Th1-derived IFN-γ signaling). Similar findings have been reported in previous studies of Barrett’s esophageal tissues, a premalignant condition with a high risk of progression to esophageal adenocarcinomas [35]. IL12A , known for its proinflammatory anti-tumor response, along with anti-tumor immune chemokines (e.g.…”

Section: Discussionsupporting

confidence: 88%

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

et al. 2017

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There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD and normal tissues. Somatic BRAF variants were found in 5/22 (23%) of AAH patients, 4/5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in all ever-smoker cases in the cohort (18%) exclusive of the cases with BRAF mutations. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF- mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed anti-tumor (Th1; IL12A, GZMB) and elevated pro-tumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways of AAH and immune dysregulation in the pathogenesis of this pre-malignant lung lesion.

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Section: Discussionsupporting

confidence: 88%

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

et al. 2017

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“…Published data regarding the role of the immune system in the development of EACs have been conflicting [6][7][8][9]. Indeed, most studies on esophageal cancer analyze esophageal adenocarcinoma and esophageal squamous cell carcinoma together.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival

Karstens

Kempski

Giannou

et al. 2020

Cancer Immunol Immunother

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Objective Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood. Methods mRNA expression levels of pro-and anti-inflammatory markers in 39 EAC patients without neoadjuvant radiochemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry. Results Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4 + T cells with a reduction in CD4 + T cells producing IL-22 or IL-17A. We also observed an increase in CD4 + CD127 low FOXP3 + cells producing IL-10. Accumulation of FOXP3 + T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis. Conclusion EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.

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“…A previous nested case–control study found nonsignificantly higher blood levels of IL‐4 in individuals who subsequently developed gastric cancer . Although there are no tissue data for advanced premalignant lesions in the stomach, the analogous condition Barrett's esophageal metaplasia is characterized by increased tissue levels of IL‐4 . Furthermore, high gastric levels of Th2 cytokines may contribute to the increased eosinophilic infiltration observed in advanced premalignant lesions .…”

Section: Discussionmentioning

confidence: 99%

“…17 Although there are no tissue data for advanced premalignant lesions in the stomach, the analogous condition Barrett's esophageal metaplasia is characterized by increased tissue levels of IL-4. 18,19 Furthermore, high gastric levels of Th2 cytokines may contribute to the increased eosinophilic infiltration observed in advanced premalignant lesions. 20 In a recent meta-analysis of candidate genetic association studies, risk of gastrointestinal cancer overall was increased with IL-4 rs2070874 T allele and decreased with its receptor IL-4R rs1801275 G allele.…”

Section: Discussionmentioning

confidence: 99%

Circulating inflammation‐related markers and advanced gastric premalignant lesions

Song

Rabkin

Torres

et al. 2018

J of Gastro and Hepatol

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Background and Aim Chronic Helicobacter pylori infection causes gastric mucosal inflammation as an important antecedent of gastric cancer. We aimed to evaluate associations of blood markers of inflammation with gastric intestinal metaplasia and dysplasia in H. pylori‐infected individuals. Methods We compared pre‐treatment serum levels of immune‐related and inflammation‐related markers between 99 individuals with intestinal metaplasia or dysplasia and 75 control individuals with non‐atrophic gastritis within an H. pylori eradication trial in Mexico. Serum levels of 28 markers measured with Luminex bead‐based assays were categorized in tertiles as low (T1), middle (T2), and high (T3). Logistic regression models were used to calculate age‐adjusted and sex‐adjusted odds ratios and 95% confidence intervals. All statistical tests were two‐sided, and significance values were adjusted for multiple comparisons using false discovery rate methods. Results Five markers were nominally associated (Ptrend < 0.05) with the presence of advanced premalignant gastric lesions. Adjusted odds ratios (95% confidence interval) of T2 and T3 versus T1 were 4.09 (1.65–10.17) and 3.08 (1.23–7.68) for CCL3/MIP1A, 3.21 (1.33–7.75) and 2.69 (1.10–6.57) for CCL20/MIP3A levels, 1.79 (0.77–4.18) and 2.39 (1.02–5.60) for IL‐1β, 1.34 (0.56–3.19) and 3.02 (1.29–7.12) for IL‐4, and 1.07 (0.44–2.59) and 3.07 (1.32–7.14) for IL‐5, respectively. Two (IL‐4 and IL‐5) of the five markers had false discovery rate adjusted Ptrend < 0.2. Conclusions Our results suggest that certain Th2 and other cytokines may have a role in promoting carcinogenesis in the setting of H. pylori infection. Additional research is needed to replicate these findings, extend to pre‐diagnostic samples, and elucidate the underlying mechanisms.

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Impact of the inflammatory microenvironment on T-cell phenotype in the progression from reflux oesophagitis to Barrett oesophagus and oesophageal adenocarcinoma

Cited by 48 publications

References 28 publications

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival

Circulating inflammation‐related markers and advanced gastric premalignant lesions

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