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Physically Inactivated Tumor Organoids Enable Rapid and Personalized Enrichment of Cytotoxic T Cells for Solid Tumor
Yu Zhang1, Haoran Zhao2, Junhong Zeng1
1Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen, China.
Abstract:
Adoptive T cell therapy holds great promise for the treatment of solid tumors but remains constrained by tumor heterogeneity, inefficient neoantigen targeting, and the complexity of T cell manufacturing. Here, we present a patient-specific, broadly applicable platform using physically inactivated tumor organoids (PIOs) to generate tumor-specific cytotoxic T cells ex vivo. Derived from droplet-engineered tumor organoids (DEOs), PIOs preserve the full antigenic repertoire of the patient's tumor without requiring synthetic peptides, antigen-presenting cells, or neoantigen prediction. Using matched tumor tissue and PBMCs from colorectal and liver cancer patients, we show that PIOs activate and expand tumor-specific T cells with enhanced infiltration, selective cytotoxicity, and robust secretion of IFN-γ and IL-2. Multi-round PIO stimulation achieves 80-400-fold expansion of CD8+CD137+ T cells within two weeks. Transcriptomic and epigenetic profiling suggest that PIOs modulate T cell programs linked to migration and persistence. This work redefines tumor organoids as immunotherapeutic materials and establishes a rapid, cost-effective platform for personalized T cell manufacturing. Our findings provide a new translational route for adoptive cell therapy in solid tumors using patient-derived materials.
Insights
Physically inactivated tumor organoids (PIOs) offer a novel platform for generating patient-specific T cells for cancer therapy. This method enhances T cell expansion and function, providing a cost-effective approach for personalized adoptive cell therapy.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Adoptive T cell therapy shows potential for solid tumors but faces challenges like tumor heterogeneity and manufacturing complexity.
- Current methods often rely on synthetic peptides or neoantigen prediction, limiting broad applicability.
Purpose of the Study:
- To develop a patient-specific platform using physically inactivated tumor organoids (PIOs) for generating tumor-specific cytotoxic T cells ex vivo.
- To overcome limitations in neoantigen targeting and T cell manufacturing for solid tumor treatment.
Main Methods:
- Droplet-engineered tumor organoids (DEOs) were used to create PIOs, preserving the full tumor antigenic repertoire.
- Matched tumor tissue and peripheral blood mononuclear cells (PBMCs) from colorectal and liver cancer patients were utilized.
- Multi-round PIO stimulation was employed to expand T cells.
Main Results:
- PIOs successfully activated and expanded tumor-specific T cells, demonstrating enhanced infiltration, selective cytotoxicity, and cytokine secretion (IFN-γ, IL-2).
- An 80-400-fold expansion of CD8+CD137+ T cells was achieved within two weeks.
- Transcriptomic and epigenetic analyses indicated PIOs modulate T cell programs related to migration and persistence.
Conclusions:
- Physically inactivated tumor organoids (PIOs) serve as effective immunotherapeutic materials for personalized T cell manufacturing.
- This platform offers a rapid, cost-effective, and broadly applicable approach for adoptive cell therapy in solid tumors.
- The study presents a new translational strategy using patient-derived materials for enhanced cancer treatment.
