Treg-Mediated Immune Tolerance and the Risk of Solid Cancers: Findings From EPIC-Heidelberg

Barth, Sebastian; Schulze, Janika; Kühn, Tilman; Raschke, Eva; Hüsing, Anika; Johnson, Theron; Kaaks, Rudolf; Olek, Sven

doi:10.1093/jnci/djv224

Cited by 33 publications

(37 citation statements)

References 50 publications

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“…19,42 Indeed, a high ratio of FOXP3 + Treg cells and CD3 + T cells has been shown to predict CRC risk. 43 The number of FOXP3 + Treg cells is higher in human CRC than in surrounding unaffected mucosa, 44-46 and an enhanced infiltration of FOXP3 + Treg cells has been detected in MSI-high CRCs compared to MSS cancers. 31,47 Moreover, in mouse models transient ablation of Foxp3 + Treg cells has been shown to decrease colorectal tumor burden through expansion of CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Marine ω-3 Polyunsaturated Fatty Acid Intake and Risk of Colorectal Cancer Characterized by Tumor-Infiltrating T Cells

et al. 2016

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Importance Marine ω-3 polyunsaturated fatty acids (PUFAs; including eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid) possess potent immunomodulatory activity and may protect against cancer development. However, evidence relating marine ω-3 PUFAs to colorectal cancer risk remains inconclusive. Objective To test the hypothesis that marine ω-3 PUFA intake may be associated with lower risk of colorectal cancer subsets characterized by immune infiltrate. Design Prospective cohort study Setting Nurses' Health Study (1984-2010) and Health Professionals Follow-up Study (1986-2010) Participants Among 173,229 predominantly white participants, 125,172 provided data about marine ω-3 PUFA intake every 4 years through a validated food frequency questionnaire and followed up for incident colorectal cancer. We documented 614 colorectal cancer cases from which we could assess T-cell infiltration in the tumor microenvironment. Cause-specific Cox proportional hazards regression was used to estimate hazard ratios for risks of colorectal cancer subtypes. Exposure Intake of marine ω-3 PUFAs Main Outcome and Measures Incidence of colorectal cancer according to CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ T-cell densities in tumor tissue, measured by immunohistochemistry and computer-assisted image analysis. Results The inverse association of marine ω-3 PUFAs with colorectal cancer risk differed according to FOXP3+ T-cell infiltration (P for heterogeneity = 0.006). Compared to intake of <0.15 g/day of marine ω-3 PUFAs, intake of ≥0.35 g/day was associated with a multivariable hazard ratio of 0.57 (95% confidence interval, 0.40 to 0.81) (P for trend < 0.001) for FOXP3+ T-cell-high tumors. In contrast, the corresponding hazard ratio was 1.14 (95% confidence interval, 0.81 to 1.60) (P for trend = 0.77) for FOXP3+ T-cell-low tumors. No statistically significant differential association was found according to CD3+, CD8+, or CD45RO+ cell density (P for heterogeneity ≥ 0.34). In functional assays, the suppressive activity of regulatory T cells was approximately two-fold lower when pre-incubated with docosahexaenoic acid at 50, 100 and 200 μM than without docosahexaenoic acid (P<0.0001). Conclusion and Relevance High marine ω-3 PUFA intake was associated with lower risk of colorectal cancer with high-level, but not low-level, FOXP3+ T-cell density, suggesting a potential role of ω-3 PUFAs in cancer immunoprevention through modulation of regulatory T cells.

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Section: Discussionmentioning

confidence: 99%

Marine ω-3 Polyunsaturated Fatty Acid Intake and Risk of Colorectal Cancer Characterized by Tumor-Infiltrating T Cells

et al. 2016

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“…However, this attenuating effect in turn might increase susceptibility to cancer (e.g. colon cancer), and thus this issue should be considered in future studies [91]. …”

Section: Discussionmentioning

confidence: 99%

Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis

Murray

Perdew

2017

Current Opinion in Toxicology

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The Ah receptor (AHR) is capable of binding a structurally diverse group of compounds that can be found in the diet, produced by bacteria in the gut and through endogenous metabolism. The gastrointestinal tract is a rich source of AHR ligands, which have been shown to protect the gut upon challenge with either pathogenic bacteria or toxic chemicals. The human AHR can be activated by a broader range of ligands compared to the mouse AHR, suggesting that studies in mice may underestimate the impact of AHR ligands in the human gut. The protective effect of AHR activation appears to be due to modulating the immune system within the gut. While several mechanisms have been established, due to the increasingly pleotropic nature of the AHR, other mechanisms of action likely exist that remain to be identified. The major contributors to AHR function in the gut and the most appropriate level of receptor activation that maintains intestinal homeostasis warrants further investigation.

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“…The pre-existing conditions that may pre-dispose patients to develop glioblastoma may be similar to patients with increased peripheral immune tolerance and subsequent higher incidences of lung, colorectal, and estrogen receptor (ER)-negative breast cancer [30]. …”

Section: Discussionmentioning

confidence: 99%

Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine

Capper

Deimling

Brandes

et al. 2017

IJMS

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Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.

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Treg-Mediated Immune Tolerance and the Risk of Solid Cancers: Findings From EPIC-Heidelberg

Abstract: The present study indicates that increased peripheral immune tolerance may be an independent risk factor for lung, colorectal, and ER-negative breast cancer, whereas its role on the development of prostate and ER-positive breast tumors remains uncertain.

Cited by 33 publications

References 50 publications

Marine ω-3 Polyunsaturated Fatty Acid Intake and Risk of Colorectal Cancer Characterized by Tumor-Infiltrating T Cells

Marine ω-3 Polyunsaturated Fatty Acid Intake and Risk of Colorectal Cancer Characterized by Tumor-Infiltrating T Cells

Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis

Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine

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