Progressive NK cell dysfunction and ILC imbalance as drivers of immune evasion in multiple myeloma.

e19557 Background: Innate lymphoid cells (ILCs), including Natural killer (NK), exhibit distinct phenotypic and functional changes during multiple myeloma (MM) progression. These alterations impair anti-MM immunity and provide opportunities for therapeutic targeting and early biomarker discovery. Methods: We analyzed NK and ILCs in peripheral blood (PB) and bone marrow (BM) across different disease stages: monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed MM (NDMM). We enrolled 5 MGUS, 8 SMM, 6 NDMM. The study was approved by Institutional Review Boards and an Independent Ethics Committee (N.1300, 2023). PB and BM cells were isolated via gradient centrifugation, stained for flow cytometry, and analyzed using FlowJo and Cytobank. Results: NK frequency increased from asymptomatic stages to NDMM in both PB and BM, correlating with plasma cells infiltration. Analysis of NK subsets revealed an increase of CD56 dim population, known for its strong cytotoxic abilities, but its effectiveness was limited by CD16 downregulation, a key receptor for antibody-dependent cellular cytotoxicity. The emergence of a CD56 dim CD16 neg NK subset indicated a shift toward an exhausted phenotype, compromising the ability to effectively engage with therapeutic monoclonal antibodies, such as daratumumab and isatuximab. We also examined other ILC subsets during MM progression and observed a decline in total ILC frequency, especially in BM. This decrease was mainly due to a reduction in the ILC1 subset, which is similar to NK in type 1 immune responses. The significant loss of ILC1 suggests early suppression of type 1 immunity in the MM microenvironment, potentially aiding growth and immune evasion. ILC2s frequency significantly increased in both PB and BM during MM progression. Known for their role in tissue remodeling and immune regulation, ILC2s may contribute to a tumor-permissive microenvironment that facilitates disease progression. Conversely, ILC3s showed a biphasic trend, increasing during SMM but declining in NDMM. This suggests that ILC3s may help control early tumor growth in SMM, while their decline in NDMM indicates a loss of immune control. These patterns highlight the complex roles of ILC subsets, offering new avenues for therapeutic targeting. Changes in NK and ILC subsets provide important biomarkers for early disease stratification and treatment response in MM. The CD16 decreased expression in NK, loss of ILC1 in BM, and increase of ILC2 in both PB and BM may indicate MM evolution. Conclusions: We uncovered a complex and context-dependent roles between innate immune cells and MM, offering new opportunities for new targeted therapeutic approaches and exposing key vulnerabilities in the MM-immune interaction. Targeting these vulnerabilities through restoring NK functionality and modulating ILC subsets may lead to more effective therapies and improved patient outcomes.