TY - JOUR
T1 - Smoking and risk of colorectal cancer sub-classified by tumor-infiltrating T cells
AU - Hamada, Tsuyoshi
AU - Nowak, Jonathan A.
AU - Masugi, Yohei
AU - Drew, David A.
AU - Song, Mingyang
AU - Cao, Yin
AU - Kosumi, Keisuke
AU - Mima, Kosuke
AU - Twombly, Tyler S.
AU - Liu, Li
AU - Shi, Yan
AU - Da Silva, Annacarolina
AU - Gu, Mancang
AU - Li, Wanwan
AU - Nosho, Katsuhiko
AU - Keum, Nana
AU - Giannakis, Marios
AU - Meyerhardt, Jeffrey A.
AU - Wu, Kana
AU - Wang, Molin
AU - Chan, Andrew T.
AU - Giovannucci, Edward L.
AU - Fuchs, Charles S.
AU - Nishihara, Reiko
AU - Zhang, Xuehong
AU - Ogino, Shuji
N1 - Funding Information:
This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969 to MJ Stampfer, UM1 CA186107 to MJ Stampfer, P01 CA55075 to WC Willett, UM1 CA167552 to WC Willett, U01 CA167552 to WC Willett and LA Mucci, P50 CA127003 to CSF, R01 CA118553 to CSF, R01 CA169141 to CSF, R01 CA137178 to ATC, K24 DK098311 to ATC, R35 CA197735 to SO, R01 CA151993 to SO, K07 CA190673 to RN, and K07 CA188126 to XZ); by Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to SO); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. This work was additionally supported by the Stand Up to Cancer (SU2C) Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to MGi and CSF). The SU2C is a program of the Entertainment Industry Foundation, and research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C. TH was supported by a fellowship grant from the
Funding Information:
Mitsukoshi Health and Welfare Foundation. KK was supported by grants from Overseas Research Fellowship (JP2017–775) and Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, from Japan Society for the Promotion of Science. KM was supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japan Society for the Promotion of Science. LL was supported by a scholarship grant from Chinese Scholarship Council and a fellowship grant from Huazhong University of Science and Technology. NK was supported by grants from the National Research Foundation of Korea (NRF-2018R1C1B6008822 and NRF-2018R1A4A1022589).
Funding Information:
ATC previously served as a consultant for Bayer Healthcare, Pfizer Inc., and Aralez Pharmaceuticals. This study was not funded by Bayer Healthcare, Pfizer Inc., or Aralez Pharmaceuticals.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Background Evidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune response. Methods During follow-up of 134 981 participants (3 490 851 person-years) in the Nurses' Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3 + cells, CD8 + cells, CD45RO (PTPRC) + cells, or FOXP3 + cells. All statistical tests were two-sided. Results The association of smoking status with colorectal cancer risk differed by CD3 + cell density (P heterogeneity =.007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3 + cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (P trend =.002, across smoking status categories). In contrast, smoking status was not associated with CD3 + cell-high cancer risk (P trend =.52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8 + cells, CD45RO + cells, or FOXP3 + cells (P heterogeneity >.04, with adjusted α of 0.01). Conclusions Colorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.
AB - Background Evidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune response. Methods During follow-up of 134 981 participants (3 490 851 person-years) in the Nurses' Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3 + cells, CD8 + cells, CD45RO (PTPRC) + cells, or FOXP3 + cells. All statistical tests were two-sided. Results The association of smoking status with colorectal cancer risk differed by CD3 + cell density (P heterogeneity =.007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3 + cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (P trend =.002, across smoking status categories). In contrast, smoking status was not associated with CD3 + cell-high cancer risk (P trend =.52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8 + cells, CD45RO + cells, or FOXP3 + cells (P heterogeneity >.04, with adjusted α of 0.01). Conclusions Colorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.
UR - http://www.scopus.com/inward/record.url?scp=85060130533&partnerID=8YFLogxK
U2 - 10.1093/jnci/djy137
DO - 10.1093/jnci/djy137
M3 - Article
C2 - 30312431
AN - SCOPUS:85060130533
SN - 0027-8874
VL - 111
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 1
M1 - djy137
ER -