Dissecting the mechanisms of Multiple Myeloma (MM) resistance to Natural Killer (NK) cells and the role of NK cells-macrophage interaction in MM immune-evasion

Description

The study aims to investigate mechanisms of Multiple Myeloma (MM) resistance to Natural Killer (NK) cells and the role of NK cells’ interaction with macrophages in immune evasion. Aim 1 focuses on validating candidate NK cell resistance genes identified from previous functional genomic screens, using CRISPR editing and activation techniques on MM cell lines. This includes in vitro validation using single gene knockouts and pooled CRISPR screening with single-cell transcriptome readout. Additionally, multiplexed single-cell RNA sequencing will be employed to study NK cell transcriptome changes when challenged with different MM cell knockouts.

Aim 2 aims to define the impact of macrophage polarization on NK cell tumor infiltration and identify compounds that can modulate macrophage polarization. This includes multiplexed imaging on bone marrow biopsies to understand the spatial organization of the immune microenvironment and in vitro experiments to assess NK cell migration in the presence of polarized macrophages. Furthermore, a high-throughput drug screen will be conducted to identify compounds that can potentially enhance NK cell therapy effectiveness by modulating macrophage polarization. Validated compounds will be profiled using single-cell RNA sequencing. Overall, the study seeks to unravel key pathways involved in MM immune evasion and explore potential therapeutic targets.