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

Mayte Coiras^1*Clara Sánchez-Menéndez¹Jaime Rodríguez-Pérez¹Daniel Fuertes²Valentina Leguizamon¹María González-Sanmartin¹Elena Mateos¹Miguel Cervero³Esther San Jose⁴Gonzalo Sanz⁵Edurne Álvaro⁶Araceli Ballestero-Pérez⁷Marc Martí-Gallostra⁸José Antonio Rueda⁹Elena Hurtado-Caballero¹⁰Carlos Pastor¹¹Francesc Balaguer¹²Antonino Spinelli¹³Jorge Martínez-Laso¹Montserrat Torres¹JOSE PEREA¹⁴

• ¹Carlos III Health Institute (ISCIII), Madrid, Spain
• ²Universidad Politecnica de Madrid Escuela Tecnica Superior de Ingenieros de Telecomunicacion, Madrid, Spain
• ³Universidad Alfonso X el Sabio, Villanueva de la Cañada, Spain
• ⁴Universidad Europea de Madrid SLU, Madrid, Spain
• ⁵Hospital Clinico San Carlos, Madrid, Spain
• ⁶Hospital Universitario Infanta Leonor, Madrid, Spain
• ⁷Hospital Universitario Ramon y Cajal, Madrid, Spain
• ⁸Hospital Universitari Vall d'Hebron, Barcelona, Spain
• ⁹Hospital Universitario Fundacion Alcorcon, Alcorcón, Spain
• ¹⁰Hospital General Universitario Gregorio Maranon, Madrid, Spain
• ¹¹Universidad de Navarra, Pamplona, Spain
• ¹²Hospital Clinic de Barcelona, Barcelona, Spain
• ¹³Humanitas University, Milan, Italy
• ¹⁴Instituto de Investigacion Biomedica de Salamanca, Salamanca, Spain

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. 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. 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 IFNγ, IL-9, and IL-17A, respectively, and increased plasma levels of IFNγ 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+ Tγδ and Th22 cells, and increased plasma CCL13/MCP-4, consistent with tissue remodeling and immune suppression. Biomarkers distinguishing EOCRC included reduced Th22 and CD8+ Tγδ cell frequencies and higher NKT-like cells with increased IL-13 production by Th22 cells. 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.