Pathogen-Boosted Adoptive Cell Transfer Therapy Induces Endogenous Antitumor Immunity through Antigen Spreading

Area of Science:

• Immunology
• Cancer Research
• Cell Therapy

Background:

• Adoptive cell therapy (ACT) faces challenges due to tumor cell antigen loss.
• Broadening immune response to multiple tumor-associated antigens (TAAs) is key to overcoming this limitation.

Purpose of the Study:

• To evaluate the efficacy of Re-energized ACT (ReACT) in preventing antigen loss variants.
• To investigate the role of Batf3-driven cDC1s in ReACT-mediated antitumor responses.
• To assess the generation of memory T cells and long-term protection against tumor recurrence.

Main Methods:

• Utilized ReACT, combining pathogen-based immunotherapy with ACT.
• Employed a B16-F10 melanoma mouse model.
• Conducted selective depletion experiments to identify key immune cell populations (Batf3-driven cDC1s).

Main Results:

• ReACT induced endogenous CD8+ T-cell responses targeting additional TAAs, preventing antigen loss variant outgrowth.
• Batf3-driven cDC1s were essential for activating endogenous tumor-specific CD8+ T cells.
• ReACT treatment led to the generation of memory CD8+ T cells, enabling rejection of subsequent tumor challenges.

Conclusions:

• ReACT provides broader TAA coverage, countering antigen escape in ACT.
• This strategy generates a durable memory response against local relapse and metastasis.
• ReACT offers a promising approach to enhance the efficacy and durability of cancer immunotherapy.