Abstract 2733: Smoking and colorectal cancer Iincidence by tumor microenvironment in cancer tissue
Authors: Ugai Tomotaka , Väyrynen Juha P. , Haruki Koichiro , Akimoto Naohiko , Lau Mai Chan , Zhong Rong , Väyrynen Sara A. , Zhao Melissa , Costa Andressa Dias , Borowsky Jennifer , Guerriero Jennifer L. , Fuchs Charles S. , Zhang Xuehong , Wang Molin , Giannakis Marios , Meyerhardt Jeffrey A. , Nowak Jonathan A. , Ogino Shuji 
Published: July 2021

Abstract
Background: Biological evidence indicates that smoking influences immune responses through interacting with various immune cell populations. We therefore hypothesized that the association of smoking with colorectal cancer (CRC) incidence differs by T-cell, tumor-associated macrophage (TAM), and myeloid cell densities.
Methods: We developed multiplexed immunofluorescence assays to identify immune cells, including T-cell subsets (CD3, CD4, CD8, CD45RO, and FOXP3), TAMs (overall, M1-like, M2-like), and myeloid cell subsets (CD14, CD15, HLA-DR, ARG) in tumor intraepithelial and stromal areas. Utilizing the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of CRC subtypes classified by each immune cell subset. We applied inverse probability weighted Cox proportional hazards regression models to control for selection bias and potential confounders.
Results: During follow-up of 131,144 participants (3,648,371 person-years), we documented 3,203 incident CRC cases including 871 CRC cases with available data on immune cell densities in tumor tissue. The association of pack-years smoked with colorectal cancer incidence was stronger for tumors with lower CD3+CD8+ T-cell densities (Pheterogeneity=0.074) and lower overall TAM densities (Pheterogeneity=0.004) in tumor stromal areas. Further, the association of pack-years smoked with colorectal cancer incidence was stronger for tumors with higher CD14+HLA-DR− immature monocytic myeloid cell densities (Pheterogeneity=0.001) in tumor intraepithelial areas.
Conclusions: The association of smoking with CRC incidence differed by stromal CD3+CD8+ T-cell densities, stromal TAM densities, and intraepithelial CD14+HLA-DR− myeloid cell densities. Our findings suggest a complex interplay of T-cells, TAMs, and myeloid cells in smoking-related colorectal carcinogenesis.
Cumulative Pack-years Smoked and Colorectal Cancer Incidence, Overall and by Immune Cell DensityCumulative Pack-years Smoked01-1920-39≥40P for trendP for heterogeneityAll colorectal cancer (N=871)361209149152--Multivariable HR (95% CI)1 (referent)1.06 (0.93-1.22)1.08 (0.92-1.25)1.25 (1.07-1.46)0.007-Stromal CD3+CD8+ cell density------Low (N=310)124685761--Multivariable HR (95% CI)1 (referent)1.07 (0.79-1.45)1.25 (0.91-1.73)1.46 (1.07-2.00)0.0120.074Intermediate (N=280)111764449--Multivariable HR (95% CI)1 (referent)1.24 (0.92-1.66)1.04 (0.73-1.47)1.38 (0.98-1.94)0.15-High (N=281)126664643--Multivariable HR (95% CI)1 (referent)0.91 (0.68-1.23)0.89 (0.64-1.26)0.98 (0.70-1.39)0.85-Stromal Macrophage density------Low (N=288)106715061--Multivariable HR (95% CI)1 (referent)1.31 (0.97-1.78)1.30 (0.92-1.84)1.70 (1.23-2.35)0.0030.004Intermediate (N=294)125605356--Multivariable HR (95% CI)1 (referent)0.82 (0.60-1.13)1.03 (0.75-1.43)1.36 (0.99-1.86)0.045-High (N=289)130784635--Multivariable HR (95% CI)1 (referent)1.12 (0.84-1.48)0.95 (0.67-1.33)0.80 (0.55-1.17)0.20-Intraepithelial CD14+HLA-DR− cell density-----Low (N=290)130763945--Multivariable HR (95% CI)1 (referent)1.08 (0.82-1.44)0.77 (0.54-1.11)0.99 (0.70-1.40)0.510.001Intermediate (N=285)120724350--Multivariable HR (95% CI)1 (referent)1.04 (0.77-1.40)0.89 (0.63-1.27)1.26 (0.90-1.77)0.36-High (N=279)98596656--Multivariable HR (95% CI)1 (referent)1.18 (0.85-1.62)1.85 (1.34-2.55)1.75 (1.26-2.44)&lt;0.001-
Citation Format: Tomotaka Ugai, Juha P. Väyrynen, Koichiro Haruki, Naohiko Akimoto, Mai Chan Lau, Rong Zhong, Sara A. Väyrynen, Melissa Zhao, Andressa Dias Costa, Jennifer Borowsky, Jennifer L. Guerriero, Charles S. Fuchs, Xuehong Zhang, Molin Wang, Marios Giannakis, Jeffrey A. Meyerhardt, Jonathan A. Nowak, Shuji Ogino. Smoking and colorectal cancer Iincidence by tumor microenvironment in cancer tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2733.