Pathological insights of human CD34+ hematopoietic stem cell-engrafted NSG mice: Implications for the safety assessment of cancer immunotherapy drugs

Humanized mice engrafted with human CD34+ hematopoietic stem cells (HSCs) are invaluable models for the preclinical evaluation of cancer immunotherapy drugs, helping to bridge the gap between <i>in vitro</i> studies and clinical trials. However, there are inherent challenges associated with these models, which require careful consideration, as they can obscure the distinction between treatment-related effects and model-specific background lesions. Here, we provide a comprehensive overview of common histopathological changes in such models, focusing on humanized nonobese diabetic (NOD) Cg-<i>Prkdc</i>^<i>scid</i> <i>Il2rg</i>^{<i>tm1Wjl/SzJ</i>} (huNSG) mice engrafted with human CD34+ HSCs. We characterize engraftment kinetics and histopathological changes at various timepoints post-engraftment and provide examples of huNSG mice utilized to evaluate immuno-oncology compounds and how these drugs influenced the development of huNSG-related background lesions. Flow cytometry and immunohistochemistry analyses reveal dynamic changes in human immune cell populations, with a predominance of B cells over T cells at early timepoints, shifting to T cell predominance at later stages. Notably, spontaneous granulomatous lesions, dominated by human macrophages, are observed in multiple organs, which increase in incidence and severity over time. These lesions are exacerbated by immunostimulatory treatments, highlighting the need for careful interpretation of drug-induced effects vs model-specific background pathology. Additionally, bone marrow necrosis that resembles ischemic lesions is identified in some huNSG mice, particularly following immune stimulation. Our findings underscore the critical importance of understanding the inherent pathological changes in huNSG mice to accurately assess the safety of cancer immunotherapy drugs.