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Updated: May 16, 2026
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Published on: September 6, 2024
Tumor immune microenvironment reconstitution in patient-derived organoids enables therapy modeling for NSCLC
Enrique Podaza1, Jared Capuano2, Hui-Hsuan Kuo2
1Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA.
Abstract:
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Despite various therapeutic options, treatment resistance is common, underscoring the need for effective combination therapies and reliable pre-clinical models for patient-specific evaluation. Here, we describe strategies for reconstituting tumor immune microenvironment (TIME) components within patient-derived tumor organoid (PDTO) cultures. We established a tumor processing pipeline that enables concurrent expansion of tumor-infiltrating lymphocytes (TILs) and PDTO generation from the same resection. We optimized scalable assays to assess IFN-γ secretion and T cell cytotoxicity with immune checkpoint inhibitors (alone or in combination) and targeted inhibitors, capturing inter-patient heterogeneity and intra-patient variations between TILs and peripheral blood mononuclear cells (PBMCs). Additionally, we developed methods for differentiating PDTO-specific tumor-associated macrophages (TAMs) and established PDTO-TAM co-culture systems to evaluate TAM effects on PDTO growth and chemotherapy sensitivity. All approaches are scalable to high-throughput levels, highlighting the value of TIME-PDTO co-cultures for therapeutic modeling and precision medicine.
Insights
Researchers developed a method to combine patient-derived tumor organoids (PDTOs) with tumor immune microenvironment (TIME) components. This approach models non-small cell lung cancer (NSCLC) treatment responses for precision medicine.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Non-small cell lung cancer (NSCLC) causes significant mortality, with frequent treatment resistance.
- Effective combination therapies and patient-specific pre-clinical models are crucial for NSCLC treatment.
- Current models often lack the complexity of the tumor immune microenvironment (TIME).
Purpose of the Study:
- To develop a method for reconstituting TIME components within patient-derived tumor organoids (PDTOs).
- To establish scalable assays for evaluating therapeutic responses in a TIME-PDTO co-culture system.
- To enable patient-specific therapeutic evaluation for precision medicine in NSCLC.
Main Methods:
- Established a pipeline for concurrent expansion of tumor-infiltrating lymphocytes (TILs) and PDTO generation.
- Developed scalable assays for IFN-γ secretion and T cell cytotoxicity using immune checkpoint inhibitors and targeted agents.
- Created methods for differentiating and co-culturing PDTO-specific tumor-associated macrophages (TAMs) with PDTOs.
Main Results:
- Successfully reconstituted TIME components within PDTOs from NSCLC patient resections.
- Captured inter-patient heterogeneity and intra-patient variations in therapeutic responses.
- Demonstrated the utility of PDTO-TAM co-cultures in evaluating TAM effects on tumor growth and chemotherapy sensitivity.
Conclusions:
- TIME-PDTO co-cultures provide a robust platform for pre-clinical therapeutic modeling in NSCLC.
- This approach facilitates patient-specific evaluation of combination therapies, including immune checkpoint inhibitors.
- The scalable methodology supports high-throughput screening for precision oncology.
