Abstract 693: Calcium intake and risk of colorectal cancer according to tumor-infiltrating T cells: Results from two large U.S. prospective cohorts
Authors: Yang Wanshui , Liu Li , Keum NaNa , Qian Zhi Rong , Nowak Jonathan A. , Hamada Tsuyoshi , Song Mingyang , Cao Yin , Nosho Katsuhiko , Smith-Warner Stephanie A. , Zhang Shui , Masugi Yohei , Ng Kimmie , Kosumi Keisuke , Ma Yanan , Garrett Wendy S. , Wang Molin , Nan Hongmei , Giannakis Marios , Meyerhardt Jeffrey A. , Chan Andrew T. , Fuchs Charles S. , Nishihara Reiko , Wu Kana , Giovannucci Edward L. , Ogino Shuji , Zhang Xuehong 
Published: August 2018

Abstract
Background: The relationship between calcium intake and colorectal cancer risk remains inconclusive. Calcium may enhance T-cell proliferation and differentiation, and contribute to T cell-mediated antitumor immunity. Investigating the calcium and colorectal cancer association according to tumor immunity status may provide additional insights into the role of calcium in colorectal carcinogenesis.
Methods: We thus investigated whether the association between calcium intake and colorectal cancer risk differs by tumor subtypes according to the density of tumor-infiltrating CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells. A total of 88,509 U.S. female registered nurses from the Nurses' Health Study and 47,740 U.S. male professionals from the Health Professionals Follow-up Study were included in the analysis. Total calcium intake from food and supplemental sources was collected at baseline and every 4 years using validated food frequency questionnaires. The densities of tumor-infiltrating T-cell subsets (CD3+, CD8+, CD45RO+, or FOXP3+ cell) was assessed using immunohistochemical and computer-assisted image analysis.
Results: We identified 736 incident colorectal adenocarcinoma cases during follow-up with available data on T-cell infiltration in tumor tissue. Compared to calcium intake of &lt;600 mg/day, total calcium intake of ≥1200 mg/day was associated with multivariable hazard ratio of 0.55 (95% confidence interval, 0.36-0.84) for CD8+ Tcell-low tumors and of 1.02 (95% confidence interval, 0.67-1.55) for CD8+ T cell-high tumors. Similarly, the corresponding HRs for low vs. high T-cell tumors were 0.63 (0.42 to 0.94; ptrend=0.01) and 0.89 (0.58 to 1.35; ptrend=0.20) for CD3+; 0.58 (0.39 to 0.87; ptrend=0.006) and 1.04 (0.69 to1.58; ptrend=0.54) for CD45RO+; and 0.56 (0.36 to 0.85; ptrend=0.006) and 1.10 (0.72 to 1.67; ptrend=0.47) for FOXP3+. We note that the difference by these subtypes was not statistically significant (all p values for heterogeneity&gt;0.01, with the adjusted α of 0.01 by Bonferroni correction). Additionally, these differential associations appeared to persist regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status (MSI).
Conclusions: Higher calcium intake appears to be primarily associated with lower risk of colorectal cancer containing low densities of T cells, but not with cancers containing high densities of T cells. This finding supports a possible role of calcium in cancer immunoprevention via modulation of T-cell function.
Citation Format: Wanshui Yang, Li Liu, NaNa Keum, Zhi Rong Qian, Jonathan A. Nowak, Tsuyoshi Hamada, Mingyang Song, Yin Cao, Katsuhiko Nosho, Stephanie A. Smith-Warner, Shui Zhang, Yohei Masugi, Kimmie Ng, Keisuke Kosumi, Yanan Ma, Wendy S. Garrett, Molin Wang, Hongmei Nan, Marios Giannakis, Jeffrey A. Meyerhardt, Andrew T. Chan, Charles S. Fuchs, Reiko Nishihara, Kana Wu, Edward L. Giovannucci, Shuji Ogino, Xuehong Zhang. Calcium intake and risk of colorectal cancer according to tumor-infiltrating T cells: Results from two large U.S. prospective cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 693.