Abstract 684: Body mass index throughout adulthood and incidence of colorectal cancer subclassified by T cell, macrophage, and myeloid cell infiltrates in cancer tissue
Authors: Ugai Tomotaka , Väyrynen Juha P. , Takashima Yasutoshi , Kahaki Seyed Mostafa Mousavi , Langworthy Benjamin , Haruki Koichiro , Akimoto Naohiko , Lau Mai Chan , Zhong Rong , Väyrynen Sara A. , Zhao Melissa , Costa Andressa Dias , Borowsky Jennifer , Guerriero Jennifer L. , Zhang Xuehong , Chan Andrew T. , Wang Molin , Giannakis Marios , Meyerhardt Jeffrey A. , Giovannucci Edward L. , Nowak Jonathan A. , Ogino Shuji 
Published: June 2022

Abstract
Abstract Background: Biological evidence indicates that obesity influences immune responses, interacting with various immune cell populations via obesity-related systemic inflammation. We hypothesized that the association of obesity with colorectal cancer (CRC) incidence differed by T-cell, macrophage, and other myeloid cell infiltrates in tumor tissue.
Methods: We developed multiplexed immunofluorescence assays to identify immune cells, including T-cell (CD3, CD4, CD8, CD45RO, and FOXP3), macrophage [CD68, CD86, IRF5, MAF, and MRC1 (CD206)], and myeloid cell (CD14, CD15, HLA-DR, ARG) subsets in tumor. Utilizing the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we examined the association of body mass index (BMI) with incidence of CRC subtypes classified by each immune cell subset. We applied inverse probability-weighted Cox proportional hazards models to control for selection bias and potential confounders. We used the stringent α level of 0.005 due to multiple comparisons.
Results: During follow-up of 131,144 participants (3,648,371 person-years), we documented 3,203 incident CRC cases including 886 CRC cases with available data on immune cell densities in tumor tissue. The association of cumulative average BMI (from baseline to the most recent questionnaire cycle) with CRC incidence differed by CD15+CD33- cell (mature granulocyte) densities in tumor intraepithelial regions (Phet=0.004). Cumulative average BMI was associated with incidence of tumors with low CD15+CD33- cell densities [18.5-22.5 kg/m2: reference; 22.5-24.9 kg/m2: HR (95% CI), 1.67 (1.12-2.48); 25.0-27.5 kg/m2: 1.73 (1.14-2.61); 27.5-29.9 kg/m2: 2.06 (1.32-3.21); ≥30 kg/m2: HR, 2.26 (1.45-3.52), Ptrend&lt;0.001], but not with incidence of tumors with intermediate or high CD15+CD33- cell densities (Ptrend&gt;0.049, with the α level of 0.005). The association of young adult BMI (at age 18 for NHS and at age 21 for HPFS) with CRC incidence differed by CD15+CD33+ cell [granulocytic myeloid-derived suppressor cell (MDSC)-like phenotype] densities in tumor intraepithelial regions (Phet&lt;0.001). Young adult BMI was associated with incidence of tumors with low CD15+CD33+ cell densities [18.5-22.5 kg/m2: reference; 22.5-24.9 kg/m2: HR (95% CI), 1.18 (0.96-1.44); 25.0-27.5 kg/m2: 1.44 (1.11-1.87); ≥27.5 kg/m2: 1.88 (1.35-2.62), Ptrend&lt;0.001], but the association was attenuated for tumors with intermediate and high CD15+CD33+ cell densities (Ptrend&gt;0.087). Similar differential associations were not observed in analyses of CRC subclassified by T cell or macrophage densities.
Conclusions: The association of BMI with CRC incidence differed by intraepithelial myeloid cell densities. Our findings suggest an interplay of obesity from early life and granulocytic MDSCs/other granulocytes in colorectal carcinogenesis.
Citation Format: Tomotaka Ugai, Juha P. Väyrynen, Yasutoshi Takashima, Seyed Mostafa Mousavi Kahaki, Benjamin Langworthy, Koichiro Haruki, Naohiko Akimoto, Mai Chan Lau, Rong Zhong, Sara A. Väyrynen, Melissa Zhao, Andressa Dias Costa, Jennifer Borowsky, Jennifer L. Guerriero, Xuehong Zhang, Andrew T. Chan, Molin Wang, Marios Giannakis, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Jonathan A. Nowak, Shuji Ogino. Body mass index throughout adulthood and incidence of colorectal cancer subclassified by T cell, macrophage, and myeloid cell infiltrates in cancer tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 684.