Circulating innate lymphoid cells and IL-18 as potential immune biomarkers in thymic tumors

Daniela Claudia Maresca¹Maria Rosaria Saponaro²Evelina La Civita³Marianna Tortora⁴Benedetta Romano¹Erica Pietroluongo²Fabio Somma¹Mario Giuliano²Alberto Servetto²Giovannella Palmieri⁴Angela Ianaro¹Daniela Terracciano³Giuseppe Ercolano^1*

• ¹Universita degli Studi di Napoli Federico II Dipartimento di Farmacia, Naples, Italy
• ²Universita degli Studi di Napoli Federico II Dipartimento di Medicina Clinica e Chirurgia, Naples, Italy
• ³Universita degli Studi di Napoli Federico II Dipartimento di Scienze Mediche Traslazionali, Naples, Italy
• ⁴Regione Campania, Naples, Italy

Thymic epithelial tumors (TETs) are rare malignancies often associated with autoimmunity, but circulating immune biomarkers for risk stratification or disease monitoring are still lacking. Innate lymphoid cells (ILCs) are emerging regulators of tumor immunity, yet their involvement in TETs has not been defined. In this study, peripheral blood samples from 32 patients with histologically confirmed TETs and 20 healthy donors were analyzed by multiparametric flow cytometry to quantify ILC subsets, and serum cytokines were measured using multiplex immunoassays. Patients were stratified according to histology, disease activity, and autoimmune manifestations. TETs were characterized by an expansion of circulating ILCs, primarily due to ILC1 enrichment, which was more pronounced in patients with evidence of disease and thymic carcinoma. Elevated serum IL-18 levels were detected, particularly in thymic carcinoma, and correlated with an increase in type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. Interestingly, no parallel rise in canonical ILC1 effector cytokines, including IFN-γ, was observed, suggesting a functional uncoupling between ILC1 expansion and their expected cytokine profile. These findings delineate a distinct systemic immune signature in TETs, characterized by IL-18 upregulation and altered ILC1 dynamics, with potential implications for immune regulation in the context of autoimmunity. Circulating ILC profiling combined with IL-18 measurement may represent a promising approach for patient stratification, disease monitoring, and the development of immunomodulatory strategies in TETs.