A miniaturized-tumor culture platform for developing anti-tumor immunotherapies

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Preserving the tumor immune microenvironment (TIME) ex vivo is crucial for studying tumor-immune interactions and developing immunotherapies.
• Existing culture models struggle to maintain autologous immune cells and support high-throughput screening.

Purpose of the Study:

• To develop and validate a novel miniaturized-tumor culture (MTC) platform for high-fidelity, high-throughput modeling of the TIME.
• To identify novel therapeutic strategies for enhancing anti-PD-L1 therapy response.

Main Methods:

• Tumor tissues from mouse models and human patients were processed into fragments for the MTC platform.
• Interleukins IL-2 and IL-7 supplementation supported intra-tumoral T cell survival.
• Co-culture assays with peripheral blood mononuclear cells (PBMCs) or splenocytes assessed response to immune checkpoint blockade (ICB).
• High-throughput drug screening identified agents to re-sensitize tumors to anti-PD-L1 therapy, with mechanistic studies using RNA-sequencing and flow cytometry.

Main Results:

• The MTC platform effectively preserved autologous lymphoid populations and maintained responsiveness to ICB.
• Co-culture assays demonstrated enhanced immune cell infiltration and recapitulated drug response/resistance phenotypes.
• Axitinib (AXI) was identified as a potent agent that re-sensitizes tumors to anti-PD-L1 therapy by enhancing antigen presentation and cytotoxic T-cell function via CXCL13 upregulation.

Conclusions:

• The MTC platform offers a high-fidelity, high-throughput tool for modeling the tumor immune microenvironment.
• This platform facilitates the development of novel anti-cancer strategies and the elucidation of their mechanisms of action.