TY - JOUR
T1 - Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer
AU - Ugai, Tomotaka
AU - Väyrynen, Juha P.
AU - Lau, Mai Chan
AU - Borowsky, Jennifer
AU - Akimoto, Naohiko
AU - Väyrynen, Sara A.
AU - Zhao, Melissa
AU - Zhong, Rong
AU - Haruki, Koichiro
AU - Dias Costa, Andressa
AU - Fujiyoshi, Kenji
AU - Arima, Kota
AU - Wu, Kana
AU - Chan, Andrew T.
AU - Cao, Yin
AU - Song, Mingyang
AU - Fuchs, Charles S.
AU - Wang, Molin
AU - Lennerz, Jochen K.
AU - Ng, Kimmie
AU - Meyerhardt, Jeffrey A.
AU - Giannakis, Marios
AU - Nowak, Jonathan A.
AU - Ogino, Shuji
N1 - Funding Information:
J.A.M. has received institutional research funding from Boston Biomedical, has served as an advisor/consultant to COTA Healthcare, and served on a grant review panel for the National Comprehensive Cancer Network funded by Taiho Pharmaceutical. M.G. receives research funding from Bristol-Myers Squibb, Merck, and Servier. This study was not funded by any of these commercial entities. A.T.C. previously served as a consultant for Bayer Healthcare and Pfizer Inc. This study was not funded by Bayer Healthcare or Pfizer Inc. C.S.F. is currently employed by Genentech, a subsidiary of Roche, and previously served as a consultant for Agios, Bain Capital, Bayer, Celgene, Dicerna, Five Prime Therapeutics, Gilead Sciences, Eli Lilly, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer Inc, Sanofi, Taiho, and Unum Therapeutics; C.S.F. also serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. No other conflicts of interest exist. The other authors declare that they have no conflicts of interest.
Funding Information:
This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; U01 CA167552 to W.C. Willett and L.A. Mucci; P50 CA127003 to C.S.F.; R01 CA118553 to C.S.F.; R01 CA169141 to C.S.F.; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; R01 CA248857 to S.O.;K07 CA188126 to X.Z., and R01 CA225655 to J.K.L.; R37 CA246175 to Y.C.); by Cancer Research UK’s Grand Challenge Initiative (UK C10674/A27140 to K.N., M.G., and S.O.); by Nodal Award (2016–20) from the Dana-Farber Harvard Cancer Center (to S.O.); by Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to C.S.F. and M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C; 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 and SU2C. K.F. was supported by fellowship grants from Uehara Memorial Foundation and Grant of The Clinical Research Promotion Foundation (2018). T.U. was supported by fellowship grants from Uehara Memorial Foundation and Yasuda Medical Foundation. K.A. and T.U. were supported by a grant from Overseas Research Fellowship from Japan Society for the Promotion of Science (201860083 to K.A.; 201960541 to T.U.). K.H. was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. M.G. is supported by an ASCO Conquer Cancer Foundation Career Development Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/4
Y1 - 2022/4
N2 - Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 “early onset,” 50–54 “intermediate onset,” ≥ 55 “later onset”). Methods: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells. Results: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039). Conclusions: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.
AB - Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 “early onset,” 50–54 “intermediate onset,” ≥ 55 “later onset”). Methods: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells. Results: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039). Conclusions: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.
KW - Colorectal neoplasms
KW - Immunology
KW - Molecular pathological epidemiology
KW - Young onset
UR - http://www.scopus.com/inward/record.url?scp=85115067081&partnerID=8YFLogxK
U2 - 10.1007/s00262-021-03056-6
DO - 10.1007/s00262-021-03056-6
M3 - Article
C2 - 34529108
AN - SCOPUS:85115067081
SN - 0340-7004
VL - 71
SP - 933
EP - 942
JO - Cancer Immunology Immunotherapy
JF - Cancer Immunology Immunotherapy
IS - 4
ER -