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

UNLABELLED

Radioimmunotherapy (RIT) is used to treat patients with hematological 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. While RIT is effective at delivering radiation to cancer cells, normal tissue is also exposed to radiation upon RIT, the consequences of which are largely unknown. Here, we studied the cellular and molecular effects of CD45-targeted astatine-211 ( At) RIT, IgG non-targeted At RIT, and Cesium-137 total-body irradiation (TBI) on hematopoietic cells and their BM niche in wild-type immunocompetent mice. Relative to non-targeted 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. While BM endothelial cells (ECs) do not express the CD45 antigen, CD45-targeted RIT significantly depleted BM ECs compared to non-targeted RIT or TBI. RNA sequence analysis revealed significantly different transcriptomic profiles of BM ECs from CD45-RIT-treated mice compared to non- targeted RIT or TBI. ECs from CD45-RIT-treated mice, but not TBI or IgG-RIT-treated mice, were transcriptionally enriched for TGFβ, NOTCH, and IFNα signaling pathways compared to untreated mice. Collectively, our study indicates that CD45-targeted RIT severely impacts hematopoietic and EC niche recovery compared to non- targeted 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.

KEY POINTS

CD45-targeted radioimmunotherapy more effectively suppresses the hematopoietic system than non- targeted radiation delivery.The bone marrow vascular niche is differentially reprogrammed by CD45-targeted radioimmunotherapy compared to non-targeted radiation delivery.