乳腺癌类器官作为PDX的互补临床前模型，实现免疫治疗评估

Background : Breast cancer (BC) remains a major global health challenge, with increasing incidence and mortality rates. Given the genetic, pathological, and clinical heterogeneity of BC subtypes, preclinical models that accurately reproduce tumor complexity are essential. To address this need, we established patient-derived xenograft (PDX) models alongside matched organoids (PDXO). This study aimed to demonstrate the high degree of similarity between PDX and their corresponding PDXO models in genomics and pharmacology. We validated organoids as a relevant platform for immunotherapy assessment, illustrated by the evaluation of trastuzumab, monoclonal antibody directed against HER2, in a co-culture system with immune cells. Methods: PDX models were generated by xenografting patient's tumors tissues in immunodeficient mice and serially passages into mice after the first engraftment. To generate matched PDXO models, PDX tumors were minced and enzymatically digested before murine cells depletion. Then, human epithelial isolated cells were seeded in Matrigel® and cultured in optimized medium. Molecular characterization was performed by whole exome and transcriptome sequencing. PDXs and PDXOs were subjected to equivalent pharmacological treatments. For trastuzumab efficacy evaluation, organoids were co-cultured with activated peripheral blood mononuclear cells (PBMCs) from healthy donors at several Effector:Target ratios. Organoid viability was evaluated after 72 hours of treatment. Results : PDXs and their corresponding PDXOs exhibited comparable responses to standard chemotherapies. Omics analyses revealed a high degree of mutational concordance between paired models, including shared oncogenic driver mutations such as TP53 and ATM. We further evaluated responses to HER2-targeted therapies using trastuzumab-emtansine (T-DM1) in two pairs of PDX and PDXO models differing in HER2 expression. T-DM1 demonstrated efficacy in both a HER2-positive PDX and its matched PDXO, resulting in tumor growth inhibition and organoid mortality. Furthermore, using a co-culture system of PBMCs and HER2-expressing organoids, we assessed the activity of trastuzumab. The antibody showed a clear antibody-dependent cell-mediated cytotoxicity effect against HER2-positive organoids, confirming the relevance of these models for evaluating immunotherapeutic responses. Conclusion: The establishment of a mirror biobank comprising matched PDX and PDXO models enables acceleration of early-stage drug screening and seamless in vivo validation using corresponding PDXs. Beyond pharmacological testing, organoids offer an advantage by facilitating the evaluation of immunotherapeutic strategies. Together, these complementary models provide powerful translational tools for the development of novel breast cancer therapies and open new avenues for advancing immunotherapy research.