Immunomodulatory Receptor ILT3/LILRB4 Protects Human Leukemic B Cells From Ferroptosis In Vitro

Immunoregulatory receptors determine immune cell fate by cell-intrinsic and cell-extrinsic mechanisms. In cancer, such feedback may enhance the selective advantage and immune evasion of tumor cells. Immunoglobulin-like transcript 3 (ILT3 or LILRB4) is an immunomodulatory receptor ectopically expressed on the surface of chronic lymphocytic leukemia (CLL) cells, but its role in CLL remains poorly understood. Here, we identified ILT3 as a marker of proliferating CLL cells co-expressed with immunoregulatory genes including IL-10, TNFRSF4, CD276, and IRS2. Notably, ILT3 expression is enriched in the proliferative CXCR4^lowCD5^high subset of circulating CLL cells and in tumor cells residing in the lymph node proliferative niche, linking ILT3 expression to tumor proliferative states. CRISPR/Cas9-mediated ILT3 loss reduced survival of proliferating CLL cells and induced transcriptomic signatures of metabolic distress in an in vitro model recapitulating lymph node-driven proliferation. Mechanistic studies revealed that ILT3 limits lipid peroxidation and protects CLL cells from ferroptosis, a form of lipid peroxidation-driven cell death that has emerged as a cancer vulnerability. Overall, our findings identify ILT3 as a key marker of the immunoregulatory program in proliferating CLL cells and illustrate that immunomodulatory receptors contribute to the maintenance of tumor metabolic homeostasis during human CLL cell proliferation in vitro.