Integrative Genomic, Single-Cell, and Functional Profiling of the CD48-CD244 Axis and NK-Cell Dysfunction in Multiple Myeloma
Patino-Escobar, B.; Steinbrunn, T.; Perez-Lugo, L.; Rampersaud, S.; Waller, D. D.; Geng, H.; Salangsang, F.; Paul Phojanakong, P.; Camara Serrano, J. A.; Steri, V.; Aguilar, O. A.; Mitsiades, C. S.; Wiita, A.
Show abstract
Multiple myeloma (MM) orchestrates immune evasion by subverting natural killer (NK) cell function. CD48, one of the most abundant NK-ligands on MM cells, paradoxically enhances NK-cell activation yet is associated with high-risk cytogenetics and poor patient survival. We integrated multi-omics (bulk and single-cell RNA-seq, ATAC-seq), genome-wide CRISPR-KO/a screens, and machine learning to dissect CD48 regulation and function. In human MM and V{kappa}*MYC mice scRNA-seq datasets, NK cells exhibit stepwise increases in inflammatory and exhaustion signatures and loss of cytotoxic potential as disease progresses. In vitro co-culture assays show CD48 overexpression on MM enhances initial NK-cell cytotoxicity and cytokine secretion, whereas chronic exposure leads to ex vivo NK dysfunction. In vivo, CD48-overexpressing V{kappa}*MYC tumors progress more slowly and extend host survival, while NK-cell depletion accelerates disease. These findings support a context-dependent role for CD48, potentiating acute NK responses while coexisting with chronic NK exhaustion, and suggest strategies to modulate CD48 for therapeutic benefit.
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