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

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. Conclusion: 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.