The bone marrow niche and hematopoietic system are distinctly remodeled by CD45-targeted astatine-211...

Radioimmunotherapy (RIT) is used to treat patients with hematologic malignancies known to infiltrate the bone marrow (BM) microenvironment. RIT uses target-specific monoclonal antibodies stably conjugated to radionuclides to deliver cytotoxic radiation to cells of interest. Although RIT is effective at delivering radiation to cancer cells, normal tissue is also exposed to radiation during RIT, the consequences of which are largely unknown. Here, we studied the cellular and molecular effects of CD45-targeted astatine-211 (211At) RIT, immunoglobulin G (IgG) nontargeted 211At RIT, and Cesium-137 total-body irradiation (TBI) on hematopoietic cells and their BM niche in wild-type immunocompetent mice. Relative to nontargeted RIT or TBI, CD45-targeted RIT significantly delayed hematopoietic regeneration overall in the peripheral blood and BM and reduced hematopoietic stem/progenitor cell recovery and colony-forming ability. Although BM endothelial cells (ECs) do not express the CD45 antigen, CD45-targeted RIT significantly depleted BM ECs compared to nontargeted RIT or TBI. RNA sequence analysis revealed significantly different transcriptomic profiles of BM ECs from CD45-RIT-treated mice compared to nontargeted RIT or TBI. ECs from CD45-RIT-treated mice, but not TBI- or IgG-RIT-treated mice, were transcriptionally enriched for growth factor signaling pathways compared to untreated mice. BM soluble growth factor expression remained upregulated in CD45-RIT-treated mice 28 days after treatment compared to nontreated mice. Collectively, our study indicates that CD45-targeted RIT severely affects hematopoietic and EC niche recovery compared to nontargeted approaches. Future studies are required to determine the long-term consequences of such RIT-driven effects on BM niche physiology and how BM niche reprogramming by RIT affects cancer cells.