Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer

Abstract

Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. While screening has reduced incidence in older adults, cases of early-onset CRC (EOCRC), diagnosed before age 50, are rising, highlighting the need to understand its unique biology. Immune responses, particularly T-cell infiltration measured by the tumor-based Immunoscore, are known predictors of CRC prognosis, but less is known about systemic immune differences by age at diagnosis. Methods: Peripheral blood mononuclear cells (PBMCs) from EOCRC (n=19) and late-onset CRC (LOCRC; n=19) participants recruited in Madrid (Spain) were analyzed for immune cell phenotypes, exhaustion markers, soluble cytokines, and metabolic activity. Results: Our study revealed distinct peripheral blood immune profiles differentiating EOCRC from LOCRC. EOCRC patients exhibited a heightened proinflammatory environment, with increased functional capacity of CD4+ Th1, Th9, and Th17 subsets to produce IFNg, IL-9, and IL-17A, respectively, and increased plasma levels of IFNg and CXCL8/IL-8. This suggests an active but potentially ineffective immune response. Conversely, LOCRC patients showed hallmarks of immunosenescence and chronic inflammation, including impaired cytokine production, higher frequencies of CD8+ Tgd and Th22 cells, and increased plasma CCL13/MCP-4, consistent with tissue remodeling and immune suppression. Biomarkers distinguishing EOCRC included reduced Th22 and CD8+ Tgd cell frequencies and higher NKT-like cells with increased IL-13 production by Th22 cells. Conclusions: EOCRC and LOCRC involved different immune mechanisms, where EOCRC showed an altered proinflammatory environment with preserved regulatory pathways, while LOCRC reflected age-related immune decline and inflammaging. Peripheral blood immune profiling offers a minimally invasive liquid Immunoscore for early detection and enables personalized immunotherapies for age-related immune landscapes, particularly benefiting younger individuals at risk of EOCRC.