Abstract
Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell-mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3(+), CD8(+) , CD45RO (PTPRC) (+) , or FOXP3(+) cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36-0.84; P (trend) = 0.002) for CD8(+) T-cell-low but not for CD8(+) T-cell-high tumors (HR = 1.02; 95% CI, 0.67-1.55; P (trend) = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell-infiltrated tumors were 0.63 (0.42-0.94; P (trend) = 0.01) and 0.89 (0.58-1.35; P (trend) = 0.20) for CD3(+) ; 0.58 (0.39-0.87; P (trend) = 0.006) and 1.04 (0.69-1.58; P (trend) = 0.54) for CD45RO(+) ; and 0.56 (0.36-0.85; P (trend) = 0.006) and 1.10 (0.72-1.67; P (trend) = 0.47) for FOXP3(+) , although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.