Abundance and balance of circulating leukocyte subsets and colorectal cancer survival

BACKGROUND: Cancer immunology research has traditionally focused on tumor-infiltrating leukocytes, but the role of the peripheral leukocytes remains understudied. Since tumor-infiltrating leukocytes are recruited from the blood, circulating immune profiles may provide prognostic insights obtainable before surgery, reflecting overall immune competence. METHODS: We analyzed treatment-naïve blood samples from 134 stage I-III colorectal cancer (CRC) patients using a nested case-control design (33 recurrences, 45 deaths; median follow-up: 7.4 years). Circulating leukocyte subsets were estimated using methylation cytometry applied to genome-wide methylation profiles. Cox regression models estimated associations between leukocyte metrics and disease-free and overall survival, adjusting for clinical factors. RESULTS: Higher counts of circulating neutrophils and T-regulatory cells were associated with worse disease-free and overall survival (neutrophil, disease-free HR: 1.32, 95% CI: 1.01, 1.72, P = 0.04; overall HR: 1.39, 95% CI: 1.00, 1.94, P = 0.05; T regulatory, disease-free HR: 1.32, 95% CI: 1.00, 1.74, P = 0.05; overall HR: 1.38, 95% CI: 1.00, 1.90, P = 0.05). Memory B cells were associated with worse disease-free survival (HR: 1.56, 95% CI: 1.31, 1.86, P < 0.0001), particularly in those diagnosed with rectal cancer. Higher basophil counts and proportions were associated with worse overall survival (count HR: 1.44, 95% CI: 1.05, 1.99, P = 0.02; proportion HR: 1.47, 95% CI: 1.06, 2.03, P = 0.02), with stronger associations in those diagnosed at earlier stages or with rectal tumors. CONCLUSIONS: Peripheral immune cell composition identifies CRC patients at higher risk for recurrence and death, providing insights into systemic immune contributions to CRC survival.