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Cancer Prev Res (Phila). 2019 May;12(5):283-294. doi: 10.1158/1940-6207.CAPR-18-0279. Epub 2019 Feb 13.

Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells.

Yang W#1,2, Liu L#3,4,5, Keum N4,6, Qian ZR3, Nowak JA7,8, Hamada T3, Song M4,9,10, Cao Y4,9,10,11, Nosho K3, Smith-Warner SA2,4, Zhang S8, Masugi Y3, Ng K8, Kosumi K3, Ma Y12,13, Garrett WS14, Wang M15, Nan H16,17, Giannakis M7,18, Meyerhardt JA7, Chan AT2,9,11,18, Fuchs CS19,20,21, Nishihara R3,4,5,8,15,18, Wu K4, Giovannucci EL4,5, Ogino S#22,5,8,18, Zhang X#23.

Author information

1
Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, Anhui, P.R. China.
2
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
4
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
5
Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, P.R. China.
6
Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea.
7
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
8
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
9
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
10
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
11
Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri.
12
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
13
Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, P.R. China.
14
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
15
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
16
Department of Epidemiology, Richard M. School of Public Health, Indianapolis, Indiana.
17
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
18
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
19
Department of Medical Oncology, Yale Cancer Center, New Haven, Connecticut.
20
Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
21
Department of Medical Oncology, Smilow Cancer Hospital, New Haven, Connecticut.
22
Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. xuehong.zhang@channing.harvard.edu sogino@bwh.harvard.edu.
23
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. xuehong.zhang@channing.harvard.edu sogino@bwh.harvard.edu.
#
Contributed equally

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.

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