Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer

Tomotaka Ugai^#^{1

2}, Juha P Väyrynen^{1

3

4}, Mai Chan Lau¹, Jennifer Borowsky^#⁵, Naohiko Akimoto¹, Sara A Väyrynen³, Melissa Zhao¹, Rong Zhong^{1

2}, Koichiro Haruki¹, Andressa Dias Costa¹, Kenji Fujiyoshi¹, Kota Arima¹, Kana Wu⁶, Andrew T Chan^{7

8

9

10}, Yin Cao^{11

12

13}, Mingyang Song^{6

8

9}, Charles S Fuchs^{14

15

16

17}, Molin Wang^{2

7

18}, Jochen K Lennerz¹⁹, Kimmie Ng³, Jeffrey A Meyerhardt³, Marios Giannakis^#^{3

20

21}, Jonathan A Nowak¹, Shuji Ogino^#^{22

23

24

25}

Affiliations

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 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴ Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland.
⁵ Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA.
¹² Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
¹³ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁴ Yale Cancer Center, New Haven, CT, USA.
¹⁵ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁶ Smilow Cancer Hospital, New Haven, CT, USA.
¹⁷ Genentech, South San Francisco, CA, USA.
¹⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁹ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²² 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.
²³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. sogino@bwh.harvard.edu.
²⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. sogino@bwh.harvard.edu.
²⁵ Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA. sogino@bwh.harvard.edu.

^# Contributed equally.

PMID: 34529108
PMCID: PMC8924022
DOI: 10.1007/s00262-021-03056-6

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer

Tomotaka Ugai et al. Cancer Immunol Immunother. 2022 Apr.

. 2022 Apr;71(4):933-942.

doi: 10.1007/s00262-021-03056-6. Epub 2021 Sep 16.

Authors

Affiliations

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 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴ Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland.
⁵ Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA.
¹² Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
¹³ Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁴ Yale Cancer Center, New Haven, CT, USA.
¹⁵ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁶ Smilow Cancer Hospital, New Haven, CT, USA.
¹⁷ Genentech, South San Francisco, CA, USA.
¹⁸ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁹ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²² 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.
²³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. sogino@bwh.harvard.edu.
²⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. sogino@bwh.harvard.edu.
²⁵ Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA. sogino@bwh.harvard.edu.

^# Contributed equally.

PMID: 34529108
PMCID: PMC8924022
DOI: 10.1007/s00262-021-03056-6

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.

Keywords: Colorectal neoplasms; Immunology; Molecular pathological epidemiology; Young onset.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig. 1**
Flow diagram of study population in the Nurses’ Health Study and the Health Professionals Follow-up Study

**Fig. 2**
Representative images of immune profiling of a colorectal adenocarcinoma using three multiplex immunofluorescence assays combined with digital image analysis. The scale bars are 100 µm

See this image and copyright information in PMC

References

1. Kamal Y, Schmit SL, Frost HR, Amos CI. The tumor microenvironment of colorectal cancer metastases: opportunities in cancer immunotherapy. Immunotherapy. 2020;12:1083–1100. doi: 10.2217/imt-2020-0026. - DOI - PMC - PubMed
1. Kather JN, Halama N. Harnessing the innate immune system and local immunological microenvironment to treat colorectal cancer. Br J Cancer. 2019;120:871–882. doi: 10.1038/s41416-019-0441-6. - DOI - PMC - PubMed
1. Ogino S, Nowak JA, Hamada T, et al. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine. Gut. 2018;67:1168–1180. doi: 10.1136/gutjnl-2017-315537. - DOI - PMC - PubMed
1. Pages F, Mlecnik B, Marliot F, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391:2128–2139. doi: 10.1016/S0140-6736(18)30789-X. - DOI - PubMed
1. Ling A, Edin S, Wikberg ML, Oberg A, Palmqvist R. The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues. Br J Cancer. 2014;110:2551–2559. doi: 10.1038/bjc.2014.161. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer

Affiliations

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous