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oai:repisalud.isciii.es:20.500.12105/270562025-12-18T13:01:59Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_16960col_20.500.12105_16961col_20.500.12105_16988

00925njm 22002777a 4500 dc Sánchez-Menéndez, Clara author Rodríguez-Pérez, Jaime author Fuertes, Daniel author Leguizamon, Valentina author González-Sanmartín, María author Mateos, Elena author Cervero, Miguel author San José, Esther author Sanz, Gonzalo author Álvaro, Edurne author Ballestero-Pérez, Araceli author Martí-Gallostra, Marc author Rueda, José Antonio author Hurtado-Caballero, Elena author Pastor, Carlos author Balaguer, Francesc author Spinelli, Antonino author Martinez-Laso, Jorge author Torres, Montserrat author Perea, José author Coiras, Mayte author Spanish EOCRC Consortium (SECOC) author 2025-12-04 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. Sánchez-Menéndez C, Rodríguez-Pérez J, Fuertes D, Leguizamon V, González-Sanmartín M, Mateos E, Cervero M, San José E, Sanz G, Álvaro E, Ballestero-Pérez A, Martí-Gallostra M, Rueda JA, Hurtado-Caballero E, Pastor C, Balaguer F, Spinelli A, Martínez-Laso J, Torres M, Perea J and Coiras M (2025) Differences in the peripheral blood immune landscape between earlyonset and late-onset colorectal cancer. Front. Immunol. 16:1692382. doi: 10.3389/fimmu.2025.1692382 10.3389/fimmu.2025.1692382 1664-3224 Frontiers in Immunology https://hdl.handle.net/20.500.12105/27056 Colorectal neoplasms Early diagnosis Immune response T-cell subsets Cytokine profiling Immune biomarkers Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer