Intratumoural vaccination via checkpoint degradation-coupled antigen presentation.

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Decreased cross-presentation by antigen-presenting cells leads to a lack of tumor-reactive T cells.
• Restoring T cell function within the tumor microenvironment is crucial for effective cancer immunotherapy.

Purpose of the Study:

• To develop a novel strategy for in situ T cell rejuvenation by reprogramming tumor cells.
• To engineer an intratumoral vaccination chimera (iVAC) to restore anti-tumor immunity.

Main Methods:

• Developed iVAC chimeras by conjugating a PD-L1 degrader with immunogenic antigens.
• Administered iVAC intratumorally to reprogram tumor cells into antigen-presenting cells (APCs).
• Evaluated iVAC efficacy in vitro, in a humanized mouse model, and in a patient-derived tumor model using cytomegalovirus (CMV)-derived antigens.

Main Results:

• iVAC successfully reprogrammed tumor cells into APC-like cells, enhancing antigen presentation.
• This reprogramming led to potent tumor killing via reactivation of resident antigen-specific CD8+ T cells.
• The treatment remodeled the tumor microenvironment, promoting durable tumor-specific immunity.

Conclusions:

• Chemically reprogramming tumor cells to exhibit APC-like functions is a viable strategy for stimulating anti-tumor immunity.
• iVAC offers a promising new avenue for cancer immunotherapy by enhancing T cell responses within the tumor bed.