title: Treg-Mediated Immune Tolerance and the Risk of Solid Cancers: Findings From EPIC-Heidelberg.
abstract: BACKGROUND
  Laboratory-based, mechanistic, and prognosis studies suggest that a shift from antitumor immunity towards tumor-immune tolerance plays a major role in carcinogenesis. However, prospective epidemiological studies on the consequences of differing immune tolerance levels prior to clinical manifestation are missing.
  
  
  METHODS
  A case-cohort study embedded in EPIC-Heidelberg was conducted comprising incident cases of breast (n = 399), colorectal (n = 185), lung (n = 149), and prostate (n = 378) cancer, which occurred during 6.6 years of follow-up, and a subcohort (n = 807). Foxp3+ regulatory T-lymphocytes and CD3+ T-lymphocytes were measured by quantitative polymerase chain reaction-based DNA methylation analysis in prediagnostic leukocyte samples. Hazard ratios (HRs) for associations of cancer risk with the ratio of both parameters, the "cellular ratio of immune tolerance" (ImmunoCRIT), were estimated using Cox regression models. All statistical tests were two-sided.
  
  
  RESULTS
  ImmunoCRIT values were positively associated with the risk of lung (highest vs lowest tertile, HR = 1.98, 95% confidence interval = 1.06 to 3.69, P trend = .0263) and colorectal cancer (HR = 1.59, 95% CI = 0.99 to 2.54, P trend = .0069) after multivariable adjustment, but not with prostate cancer risk. Regarding breast cancer significant heterogeneity by estrogen receptor (ER) status was observed (P heterogeneity = .02), and the ImmunoCRIT was associated with the risk of ER-negative breast cancer (HR = 3.34, 95% CI = 1.52 to 7.35, P trend ≤ .001), but not ER-positive breast cancer.
  
  
  CONCLUSIONS
  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.
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Sebastian Dietmar
authors: SD
authors: Barth
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Janika Josephine
authors: JJ
authors: Schulze
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Tilman
authors: T
authors: Kühn
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Eva
authors: E
authors: Raschke
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Anika
authors: A
authors: Hüsing
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Theron
authors: T
authors: Johnson
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Rudolf
authors: R
authors: Kaaks
authors: Affiliations of authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany (SDB, TK, AH, TJ, RK); Ivana Türbachova Labor für Epigenetik, Epiontis GmbH, Berlin, Germany (JJS, ER, SO).
authors: Sven
authors: S
authors: Olek
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000737:chemistry / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000276:immunology*; D019175:DNA Methylation; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance; D008175:Lung Neoplasms / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000276:immunology*; D011960:Receptors, Estrogen / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D011960:Receptors, Estrogen