Tomotaka Ugai1,2, Jennifer Borowsky3, Marios Giannakis4,5,6, Shuji Ogino7,8,9,10, Juha P Väyrynen1,4,11, Mai Chan Lau1, Naohiko Akimoto1, Sara A Väyrynen4, Melissa Zhao1, Rong Zhong1,2, Koichiro Haruki1, Andressa Dias Costa1, Kenji Fujiyoshi1, Kota Arima1, Kana Wu12, Andrew T Chan13,14,15,16, Yin Cao17,18,19, Mingyang Song12,14,15, Charles S Fuchs20,21,22,23, Molin Wang2,13,24, Jochen K Lennerz25, Kimmie Ng4, Jeffrey A Meyerhardt4, Jonathan A Nowak1. 1. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA. 2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3. Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 4. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 5. Broad Institute of MIT and Harvard, Cambridge, MA, USA. 6. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 7. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA. sogino@bwh.harvard.edu. 8. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. sogino@bwh.harvard.edu. 9. Broad Institute of MIT and Harvard, Cambridge, MA, USA. sogino@bwh.harvard.edu. 10. Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA. sogino@bwh.harvard.edu. 11. Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland. 12. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 13. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 14. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 15. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. 16. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 17. Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA. 18. Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. 19. Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. 20. Yale Cancer Center, New Haven, CT, USA. 21. Department of Medicine, Yale School of Medicine, New Haven, CT, USA. 22. Smilow Cancer Hospital, New Haven, CT, USA. 23. Genentech, South San Francisco, CA, USA. 24. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 25. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Abstract
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.
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.
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