Loss of EOMES in T Cells Accelerates Tumor Burden and Mortality in Middle Aged Mice 2250481

Abstract

Abstract Introduction Aging profoundly reshapes the immune system, leading to impaired pathogen defense, increased cancer incidence, and chronic inflammation that drives tissue dysfunction. Among immune cells, T lymphocytes undergo one of the most pronounced age-related shifts, losing naïve populations and accumulating cytokine-producing memory cells. EOMES is a transcription factor essential for effector and virtual memory CD8+ T-cell differentiation and cytotoxic activity. EOMES+ T cells accumulate with age and contribute to tissue inflammation through sustained production of IFN-γ and other inflammatory mediators. While these cells may exacerbate sterile inflammation, their role in maintaining tumor immunosurveillance during aging remains poorly defined. To determine how EOMES+ T cells contribute to age-related inflammation and tissue dysfunction, we generated T-cell—specific Eomes knockout mice (CD8a-Cre; Eomes fl/fl) and aged them alongside wild-type littermates. Methods Lifespan, organ pathology, and immune phenotypes were assessed by necropsy, histology, flow cytometry, and multiplex immunohistochemistry for CD3, CD20, and Iba1. Results Contrary to our hypothesis that EOMES deletion would preserve a youthful T-cell profile, by 15 months of age 50% of Eomes-deficient mice had died compared with ∼15% of controls, and by 18 months survival was ∼25% versus ∼65%, respectively (P < 0.0001). Knockout mice also developed multifocal neoplasms absent in controls. Immunopathology revealed admixed Iba1+ macrophages and CD20+ B cells with minimal CD3+ T-cell neoplasia, consistent with histiocyte-rich B-cell lymphoma. Conclusion These findings demonstrate that loss of EOMES-dependent cytotoxic surveillance permits malignant transformation. We propose that although EOMES-dependent immunosurveillance is critical for tumor suppression, its persistent activation with age may also contribute to age-related chronic inflammation, possibly linking antitumor immunity to inflammaging. Funding Source NIH R01AG086447, AHA 940023 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)