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

Emerging evidence indicates that CD4⁺ T cells contribute to antitumor immunity beyond their traditional roles as helpers or regulators. However, the specific subset of CD4⁺ T cells mediating beneficial outcomes in patients with multiple myeloma remains unclear. Here, we performed single-cell RNA sequencing and T-cell receptor sequencing on CD4⁺ T cells sorted from the bone marrow of patients across the stages of myeloma progression. We identified several distinct states of CD4⁺ cytotoxic T lymphocytes (CTLs) that were significantly increased and clonally expanded in patients with myeloma. CD4⁺ CTLs displayed transcriptional and phenotypic characteristics indicative of cytotoxicity, demonstrating their ability to directly kill myeloma cells. This cytotoxicity, however, was abrogated by NKG2D blockade. Notably, the abundance of NKG2D⁺CD4⁺ CTLs correlated with improved survival in patients with myeloma. Our findings suggest that harnessing CD4⁺ CTLs could lead to novel strategies for enhancing immunotherapy outcomes in multiple myeloma.