NKG2D-mediated cytotoxicity of CD4 cytotoxic T cells in multiple myeloma 4857

Description Recent studies have highlighted a role for CD4+ T cells in antitumor immunity beyond their established helper or regulatory functions. Yet, the specific CD4+ T cell subset associated with favorable clinical outcomes in multiple myeloma remains unidentified. In this study, we conducted single-cell RNA and T cell receptor sequencing of CD4+ T cells sorted from the bone marrow of patients at different stages of myeloma progression. Our findings revealed distinct populations of cytotoxic CD4+ T lymphocytes (CTLs) that were significantly expanded and clonally proliferated in myeloma patients. These CD4+ CTLs exhibited transcriptional and phenotypic markers indicative of cytotoxic activity, displaying a capacity to directly lyse myeloma cells in response to CD3 stimulation. This cytotoxic effect was, however, suppressed upon NKG2D blockade. Importantly, a higher frequency of NKG2D+CD4+ CTLs was correlated with improved survival outcomes in myeloma patients. These results suggest that targeting CD4+ CTLs may represent a novel approach to enhance immunotherapy efficacy in multiple myeloma. Funding Sources This research was supported by Severance Hospital Research fund (SHRC) C-2023-0011; KHIDI, Ministry of Health & Welfare HI22C1826, RS-2024-00404555; NRF, Ministry of Science and ICT RS-2023-00208390, RS-2024-00359839.