Work

1121 Insights from orthotopic tumor engraftment in humanized mice

Year: 2026

Type: conference-abstract

Abstract: Background Humanized immune system (HIS) mice support engraftment of human tumors and enable evaluation of oncology therapeutics in the context of a functional human immune system. While most xenograft studies rely on subcutaneous implantation, orthotopic models may better reproduce organ-specific tumor biology, metastatic dissemination, and tumor-immune interactions. We therefore sought to establish reproducible orthotopic tumor models in HIS mice and assess their impact on disease progression and immune responses.Methods Here, five orthotopic implantation approaches were developed in immunodeficient and HIS mice, targeting the femoral bone marrow, mammary fat pad, liver, pancreas, and lung.Results All models achieved 100% tumor take and supported longitudinal monitoring by caliper measurements or bioluminescence imaging. To evaluate the impact of tumor implantation site on disease progression and immune responses, we compared orthotopic and subcutaneous engraftment of A549 cells to assess differences in tumor progression, immune dynamics and systemic effects. Orthotopic lung implantation resulted in robust primary tumor growth and frequent liver metastasis, detected in approximately 80-85% of tumor-bearing mice. Both primary lung tumors and metastatic lesions exhibited pronounced fibrosis and were infiltrated by human immune cells, including T cells and macrophages. Furthermore, orthotopic tumors promoted recruitment of all major human immune cell populations to the tumor microenvironment, with significantly greater T- and B-cell infiltration than observed in healthy lung tissue.Conclusions Collectively, these findings demonstrate that orthotopic tumor engraftment in HIS mice captures key features of human cancer progression, including organ-specific immune responses, metastatic spread, stromal remodeling, and systemic disease manifestations. Orthotopic HIS models therefore provide a clinically relevant platform for evaluating immunotherapies and studying tumor-immune interactions in settings that more closely resemble human disease.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1121