The immune profiles of high-risk colorectal cancer precursors depend on colorectal cancer screening starting age and sex

Introduction Rising trends in the incidence of early-onset colorectal cancer (EOCRC), defined as a CRC diagnosed below the age of 50 years are a global phenomenon, and young individuals more frequently present themselves with advanced or aggressive disease. The antitumor immune response by infiltrating T-lymphocytes is a key prognostic factor in CRC but has not yet been investigated in colorectal cancer precursors. The aim of this study was to characterize the immune profile of colorectal polyps of individuals at different screening starting ages as a potential driver of EOCRC tumorigenesis.

Material and Methods Individuals 44-60 years who underwent colonoscopy harboring high-risk colorectal cancer precursors (size≥10 mm, high-grade dysplasia in adenomas/dysplasia in serrated polyps) were included. Polyps were stained by immunohistochemistry for representatives of the antitumor immune response (CD3, CD8) and immune tolerance (FOXP3). The primary outcome was the association of CD3+, CD8+and FOXP+with screening participants’ age at screening, stratified by sex. Linear regression analyses were performed for our primary outcome.

Results We analyzed 115 colorectal polyps. The median age of the cohort was 56 years. Younger screening participants had a significantly higher density of CD8+T-cells (estimate for age -14.89, 95% CI -27.05; -2.73) but also a marked increase in regulatory FOXP3+lymphocytes compared to older individuals (estimate for age -5.71, 95% CI -10.43; -1). While there was no significant association with overall screening participants&apos; sex and the infiltrate of CD3+and CD8+T-cells, male individuals, especially those<50 years of age had a significantly higher density of FOXP3+cells ([Fig. 1]).

Fig. 1  density of infiltrating immune cells (CD3+, CD8+, FOXP3+) in CRC screening participants with high-risk polyps. All polyps removed by polypectomy of each individual were retrieved and stained by immunohistochemistry. The immune cell density was investigated with machine-learning based object classification models, and the resulting values were normalized to the total polyp area in mm2. P-values are reported from linear regression models adjusted for screening participants’ sex and polyp type.

Conclusion Young CRC screening participants harboring high-risk polyps display a distinct immune signature with a pronounced infiltrate of immune response-dampening FOXP3+regulatory T-cells. Men below the recommended screening age had the potentially most unfavorable immune profile with a loss of overall CD3+cells and the highest density of FOXP3+T-cells.

Publication History

Article published online:
13 May 2025