Systemic DC Activation Modulates the Tumor Microenvironment and Shapes the Long-Lived Tumor-Specific Memory Mediated...

Area of Science:

• Immunology
• Oncology
• Cancer Immunotherapy

Background:

• Reprogramming the tumor microenvironment is crucial for enhancing cancer immunotherapy efficacy.
• Dendritic cells (DC) play a key role in initiating anti-tumor immune responses.
• Current immunotherapies often face challenges with poorly immunogenic tumors.

Purpose of the Study:

• To investigate the potential of adjuvant vector cells (aAVC) in improving dendritic cell (DC) function for cancer immunotherapy.
• To evaluate the impact of aAVC therapy on the tumor microenvironment and immune responses.
• To assess the combination therapy of aAVC with PD-1 blockade for treating tumors unresponsive to PD-1 blockade alone.

Main Methods:

• Engineered adjuvant vector cells (aAVC) from NKT ligand-loaded CD1d(+) allogeneic cells transfected with tumor antigen mRNAs.
• Administered aAVC therapy to mice and analyzed the resulting immune responses and tumor microenvironment.
• Combined aAVC infusion with PD-1 blockade therapy for treatment of established tumors.

Main Results:

• aAVC therapy promoted the establishment of tertiary lymphoid structures (TLS) within the tumor microenvironment.
• TLS formation was associated with expanded antigen-specific CD8(+) T-cell clones, mobilized DCs, and normalized tumor vasculature.
• Combination therapy of aAVC and PD-1 blockade induced regression of poorly immunogenic tumors and expanded tumor-specific CD8(+) T cells.

Conclusions:

• aAVC therapy effectively reprograms the tumor microenvironment, fostering a more immunogenic milieu.
• The formation of TLS and expansion of antigen-specific T cells are key mechanisms of aAVC efficacy.
• This study provides a foundation for developing next-generation cancer vaccines and combination immunotherapies.