Abundance and balance of circulating leukocyte subsets and colorectal cancer survival

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. 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. 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. Peripheral immune cell composition identifies CRC patients at higher risk for recurrence and death, providing insights into systemic immune contributions to CRC survival.