Establishment of a humanized patient-derived xenograft mouse model of high-grade serous ovarian cancer for preclinical evaluation of combination immunotherapy

Abstract

The limited efficacy of immunotherapy in clinical trials in high-grade serous ovarian cancer (HGSOC) may improve by implementing models more reflective of human biology into preclinical studies. To address this, we developed and validated a humanized patient-derived xenograft mouse model of HGSOC. Human hematopoietic stem cells and patient-derived HGSOC were engrafted into immunodeficient mice. The mice were administered durvalumab and/or oleclumab intraperitoneally semi-weekly for five weeks. The immunotherapy was well-tolerated, though no responses occurred. Leukocytes in primary tumors were analyzed immunohistochemically, and circulating T cells were characterized using spectral flow cytometry. All tumors exhibited an immune-excluded immunophenotype. No significant inter-group differences in disease burden, intratumoral leukocyte density, or circulating T-cells were observed. In the durvalumab-only group, tumor burden significantly positively correlated with intratumoral cytotoxic and regulatory T-cell densities. This model reflects human disease biology and clinical findings, providing a robust platform for studying tumor-immune interactions and immunosuppressive mechanisms in HGSOC.