Immune Markers for Early Prediction of Adult T-Cell Leukemia in HTLV-1 Carriers

Human T-cell leukemia virus type 1 (HTLV-1) can cause adult T-cell leukemia/lymphoma (ATL), an aggressive cancer with poor outcomes. Detecting early signs of progression is difficult, and better biomarkers are needed. We studied blood samples from asymptomatic carriers (ACs), ATL patients, HAM/TSP patients, and healthy controls. We measured HTLV-1 antibody responses, plasma proteins (OX40 and sTNFR2), and T-cell markers using flow cytometry. Virus-specific CD8⁺ T-cell function and TCR diversity were tested, and plasma proteomics was performed to identify new markers. We also examined how the HTLV-1 Tax protein drives CD40L expression in cell models. Classification models were built using antibody and clinical data. ATL patients showed high levels of OX40 and sTNFR2, a distinct CCR4⁺CD26⁻CD4⁺ T-cell population, reduced CD8⁺ T-cell function, and limited TCR diversity. Proteomic profiling revealed unique signatures separating ATL from carriers. Classification models best distinguished HAM/TSP from ACs but were less accurate for ATL. Tax strongly induced CD40L expression through a pathway independent of NFAT and NF-κB. ATL is associated with specific immune and protein changes, including altered antibodies, serum biomarkers, and T-cell dysfunction. Combining these biomarkers may improve early detection and risk assessment in HTLV-1 carriers, while Tax-induced CD40L offers insight into ATL biology and potential therapeutic targets.