Humanized mouse models for renal cell carcinoma research: evaluating immune checkpoint blockade 3742

Abstract Description Renal cell carcinoma (RCC) is a highly heterogeneous and metastatic disease. Cell line-derived orthotopic xenograft (CDOX) and patient-derived orthotopic xenograft (PDOX) models in immunodeficient mice can mimic human RCC, but they lack functional immune systems, limiting studies on tumor-immune interactions. To address this, we developed humanized RCC mouse models by engrafting human peripheral blood mononuclear cells into Rag2 mice implanted with RCC cell lines (SN12K1, 786-O) or patient-derived tumors (KiCa-Pt118) tagged with Luc/RFP. Mice were treated with immune checkpoint blockade (ICB) therapies, including anti-PD-1/PD-L1 and anti-CTLA-4 antibodies (200 µg/mouse) weekly for four weeks. Tumor progression was monitored using bioluminescent imaging (BLI) and tumor weight, while the presence of human immune cells was confirmed via flow cytometry and immunohistochemistry staining. Humanization was evidenced by CD45+ human T cells in circulation and tumor infiltrating human CD3+, CD8+, and Granzyme B+ cells. Anti-PD-1/PD-L1 therapy showed tumor reduction and fewer lung metastases (p < 0.05), while anti-CTLA-4 therapy significantly decreased tumor BLI levels (p < 0.01). Tumor burden, measured by tumor weight and Ki67 expression, inversely correlated with circulating CD8+ T cells, highlighting their potential as predictive biomarkers for ICB response. This humanized RCC model provides a robust platform for studying RCC progression and testing personalized immunotherapies. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)