Composition and Functional State of T and NK Cells in the Extramedullary Myeloma Tumor Microenvironment.

Extramedullary multiple myeloma (EMM) is a high-risk feature of multiple myeloma associated with increased resistance to treatments, including modern immunotherapies, and shorter survival. The composition and functional state of immune cells within the EMM tumor microenvironment (TME) remain poorly understood. Using single-cell RNA sequencing, flow cytometry, and spatial transcriptomics, we revealed significant differences in the EMM TME compared with multiple myeloma bone marrow (BM). T and NK cells were verified as the most abundant immune subsets in the EMM TME. Compared with the BM counterparts, we found these tumors to have a significantly reduced effector-to-tumor cell ratio, a significantly lower number of CD4+ T cells, and an increased proportion of regulatory CD16- NK cells. We observed a high proportion of exhausted, tumor-reactive CD8+ T cells in roughly half of EMM tumors. Furthermore, we identified elevated expression of immune checkpoints, such as PD-1 on CD8+ T cells and KLRC1 (NKG2A) on CD16- NK cells. SIGNIFICANCE: This study characterizes the TME in EMM lesions and paired BM from patients with multiple myeloma, revealing a high proportion of less cytotoxic CD16- NK cells in EMM tumors and suggesting that direct cell-cell interactions may underlie the CD8+ T-cell exhaustion observed in a subset of these tumors.