Identification of a class of non-conventional ER-stress-response-derived immunogenic peptides

Area of Science:

• Oncology
• Immunology
• Microbiology

Background:

• Immune checkpoint blockade therapy faces challenges due to the private nature of cancer mutations, limiting neoepitope vaccine efficacy.
• Developing scalable cancer immunotherapies requires strategies that target shared tumor antigens.

Purpose of the Study:

• To investigate a novel method for inducing anti-tumor immune responses by targeting shared tumor antigens.
• To explore the potential of Salmonella infection in generating immunogenic peptides from tumor cells.

Main Methods:

• Tumor cells were infected with Salmonella to induce endoplasmic reticulum (ER) stress and membrane hemichannel opening.
• Extracellular peptides released from stressed tumor cells were analyzed using mass spectrometry.
• The immunogenicity of released peptides was assessed by their ability to prime CD8+ T cells in vitro and in vivo models (mice and dogs).

Main Results:

• Salmonella infection successfully induced ER stress and extracellular release of proteasome-generated peptides from tumor cells.
• Mass spectrometry identified 12 peptides from human melanoma cells capable of priming healthy-donor CD8+ T cells.
• These primed T cells recognized and killed human melanoma cells in vitro and in xenotransplanted models in vivo.
• The approach demonstrated efficacy in both murine melanoma and canine osteosarcoma models.

Conclusions:

• Salmonella-induced ER stress provides a mechanism for extracellular release of shared tumor antigens.
• These shared antigens can prime T cells effectively, bypassing tumor-specific neoantigens and avoiding self-tolerance.
• This strategy offers a promising, broadly applicable approach to enhance cancer immunotherapy.