建立患者来源类器官-免疫细胞共培养平台用于评估免疫肿瘤学疗法的疗效

Introduction: Tumor immunotherapy, known for its high specificity and favorable safety profile, inhibits tumor progression and prolongs patient survival by activating the immune system. However, the full potential of many immuno-oncology agents and the underlying mechanisms of therapeutic resistance remain incompletely understood. The emergence of organoid technology has not only improved the accuracy of tumor modeling but also enabled co-culture with immune cells, thereby advancing the study of tumor-immune interactions and immunotherapy evaluation. Here, we established a human tumor organoid-immune co-culture platform for assessing responses to multiple immunotherapies. Methods: We established human tumor-immune co-culture models by introducing immune components-including allogeneic PBMCs with PDX-derived organoids (PDXOs) across several cancer types. For drug efficacy assessment, above co-culture models were treated with monoclonal antibodies (mAb) to evaluate antibody-dependent cellular cytotoxicity (ADCC). Additionally, ovarian cancer (OVC) PDXOs were co-cultured with PBMCs to assess T-cell engager (TCE)-mediated, TROP2-targeted T-cell-dependent cytotoxicity (TDCC). To mitigate graft-versus-host effects associated with allogeneic PBMCs, we further developed a PDO-autologous tumor-infiltrating lymphocytes (TILs) co-culture system and used it to modeling the patient responses to immune checkpoint inhibitors (ICIs). Results: In the PDXO-PBMC co-culture system, live-cell and high-content imaging revealed that in the presence of Trastuzumab, HER2-high CRC PDXOs were effectively targeted and infiltrated by immune cells, whereas these results were not observed in HER2-low PDXO models. Similarly, Sacituzumab only induced significant ADCC in TROP2-high PDXO models. The co-culture platform also proved effective for evaluating TCEs: a TROP2xCD3 bispecific TCE significantly mediated TDCC in TROP2-high OVC PDXOs. Furthermore, screening of ICIs across multiple PDO-TILs co-culture models demonstrated that this co-culture system accurately predicted clinical treatment efficacy. Summary: We have established a versatile tumor organoid-immune co-culture platform that recapitulates key features of the tumor immune microenvironment. This platform enables efficient evaluation and validation of diverse immunotherapies, including mAbs-mediated ADCC, TCE-mediated TDCC, and the efficacy of ICIs. This biomimetic in vitro model provides a powerful tool for immuno-oncology drug screening, accelerates drug development, and offers a human-relevant alternative that circumvents species-specific limitations and animal welfare concerns associated with preclinical animal models.