Prominent immune signatures of T cells are specifically associated with indolent B-cell lymphoproliferative disorders and predict prognosis

Objectives: T cells play an essential role in controlling the development of B-cell lymphoproliferative disorders (BLPDs), but the dysfunction of T cells in BLPDs largely remains elusive. Methods: Using multiplexed flow cytometry, we quantified all major subsets of CD4⁺ helper T cells (Th) and CD8⁺ cytotoxic T cells (Tc) in 94 BLPD patients and 66 healthy controls. Statistics was utilised to rank T-cell signatures that distinguished BLPDs from healthy controls and differentially presented between indolent and aggressive categories. Results: By comparing with healthy controls, we found that the indolent but not aggressive type of BLPDs demonstrated a high degree of T-cell activation, showing the increase in type I helper T (Th1) cells and follicular B-helper T (Tfh) cells, both of which strongly associated with the enhanced differentiation of exhaustion-like effector cytotoxic CD8⁺ T cells expressing PD-1 (Tc exhaustion-like) in indolent BLPDs. Random forest modelling selected a module of T-cell immune signatures best performing binary classification of all BLPD patients. This signature module was composed of low naïve Th cells and high Th1, Tfh and Tc exhaustion-like cells which efficiently identified > 85% indolent cases and was, therefore, assigned as the Indolent Dominant Module of T-cell immune signature. In indolent BLPD patients, a strong bias towards such signatures was found to associate with clinical characteristics of worse prognosis. Conclusion: Our study identified a prominent signature of T-cell dysregulation specifically for indolent BLPDs, suggesting Th1, Tfh and Tc exhaustion-like cells represent potential prognostic biomarkers and targets for immunotherapies.