T-cell Subset Features and Distributions Evolve across the Colorectal Precancer–Cancer Spectrum

The immune microenvironment is a crucial component of colorectal carcinoma that has been well characterized, but much less is known about the immune microenvironment of colorectal carcinoma precursors. We hypothesized that T-cell infiltrates might differ across the colorectal neoplastic spectrum. We leveraged the prospective cohort incident-tumor biobank method, which provided formalin-fixed, paraffin-embedded tumor tissue specimens (N = 1,825) from 790 colorectal carcinoma precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 colorectal carcinomas. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO and CD45RA), MKI67 (Ki-67), and KRT (keratin) combined with supervised machine learning. CD3+CD4+ cells were more abundant than CD3+CD8+ cells in most precursors. In conventional adenomas, greater villous component correlated with fewer intraepithelial CD3+CD8+ cells. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, exhibited higher densities of intraepithelial CD3+CD8+ cells compared with other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared with invasive colorectal carcinoma, precursors generally showed higher densities of CD3+CD4+ cells and CD3+CD8+ cells with phenotypes of naive (CD45RA+CD45RO-), memory (CD45RA-CD45RO+), and regulatory (FOXP3+Low and FOXP3+High) in intraepithelial and lamina propria/stromal regions. In conclusion, T-cell infiltration patterns vary across different histopathologic types of the colorectal neoplastic spectrum from precursors to invasive carcinomas. Our findings shed light on how the tumor-immune microenvironment evolves during precursor development and progression to colorectal carcinoma.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-11-12
DOI
https://doi.org/10.1158/2326-6066.cir-25-0481
Citations
2
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
2.09
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article

T-cell Subset Features and Distributions Evolve across the Colorectal Precancer–Cancer Spectrum

Tomotaka Ugai, Mingyang Song, Amanda I. Phipps, Yasutoshi Takashima et al.
2 citations
Cancer Immunology Research
Cancer Immunotherapy and Biomarkers
2.09
article

T-cell Subset Features and Distributions Evolve across the Colorectal Precancer–Cancer Spectrum

Tomotaka Ugai, Mingyang Song, Amanda I. Phipps, Yasutoshi Takashima, Satoko Ugai, Koichiro Haruki, Qian Yao, Marios Giannakis, Charles S. Fuchs, Ulrike Peters, Kosuke Matsuda, Jonathan Andrew Nowak, Daniel D. Buchanan, Mayu Higashioka, Naohiko Akimoto, Andrew T. Chan, Mari A. Mino-Kenudson, Andressa Dias Costa, Shuji Ogino, Juha P. Väyrynen, Jason L. Hornick, Phoenix Bell, Yuxue Zhong
article en
2 citations

Abstract

The immune microenvironment is a crucial component of colorectal carcinoma that has been well characterized, but much less is known about the immune microenvironment of colorectal carcinoma precursors. We hypothesized that T-cell infiltrates might differ across the colorectal neoplastic spectrum. We leveraged the prospective cohort incident-tumor biobank method, which provided formalin-fixed, paraffin-embedded tumor tissue specimens (N = 1,825) from 790 colorectal carcinoma precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 colorectal carcinomas. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO and CD45RA), MKI67 (Ki-67), and KRT (keratin) combined with supervised machine learning. CD3+CD4+ cells were more abundant than CD3+CD8+ cells in most precursors. In conventional adenomas, greater villous component correlated with fewer intraepithelial CD3+CD8+ cells. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, exhibited higher densities of intraepithelial CD3+CD8+ cells compared with other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared with invasive colorectal carcinoma, precursors generally showed higher densities of CD3+CD4+ cells and CD3+CD8+ cells with phenotypes of naive (CD45RA+CD45RO-), memory (CD45RA-CD45RO+), and regulatory (FOXP3+Low and FOXP3+High) in intraepithelial and lamina propria/stromal regions. In conclusion, T-cell infiltration patterns vary across different histopathologic types of the colorectal neoplastic spectrum from precursors to invasive carcinomas. Our findings shed light on how the tumor-immune microenvironment evolves during precursor development and progression to colorectal carcinoma.

Cancer Immunology ResearchVol. 14(1)
Broad Institute (US), Jikei University School of Medicine (JP), Brigham and Women's Hospital (US), Cleveland Clinic (US), The Royal Melbourne Hospital (AU), Harvard University (US), The University of Melbourne (AU), University of Washington (US), Oulu University Hospital (FI), Harvard University Press (US), National Cancer Centre Japan (JP), Massachusetts General Hospital (US), Tokyo Institute of Psychiatry (JP), Fred Hutch Cancer Center (US), Victorian Comprehensive Cancer Centre (AU), Dana-Farber Cancer Institute (US), Kaiser Permanente South San Francisco Medical Center (US), University of Washington Applied Physics Laboratory (US), Nippon Medical School (JP), University of Oulu (FI)
Openalex Percentile: Top 10%
Cancer Immunotherapy and Biomarkers
2.09
DOISourceOpenAlex
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