Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage

Area of Science:

• Immunology
• Microbiology
• Oncology

Background:

• Intestinal microbiota may induce T cells that cross-react with tumor antigens.
• Microbial components could be leveraged to enhance cancer immunotherapy.

Purpose of the Study:

• To investigate if microbial epitopes can elicit anti-tumor T cell responses.
• To determine the role of a specific bacterial protein in cancer immunotherapy efficacy.

Main Methods:

• Identified MHC class I-binding epitopes in the tail length tape measure protein (TMP) of an Enterococcus hirae prophage.
• Administered engineered bacterial strains expressing TMP epitopes to mice undergoing immunotherapy.
• Analyzed TMP-specific CD8+ T cell responses in mice.
• Correlated enterococcal prophage presence and TMP-cross-reactive antigen expression with immunotherapy outcomes in cancer patients.

Main Results:

• Mice harboring the prophage showed TMP-specific CD8+ T cell responses upon immunotherapy.
• Engineered bacteria expressing TMP epitopes enhanced immunotherapy outcomes in mice.
• Enterococcal prophage presence and TMP-cross-reactive tumor antigens correlated with long-term benefit from PD-1 blockade therapy in renal and lung cancer patients.
• T cell clones cross-reactive with microbial peptides were detected in melanoma patients.

Conclusions:

• Commensal-derived microbial epitopes, such as TMP, can elicit anti-tumor CD8+ T cell responses.
• Engineering bacteria to express microbial epitopes can improve cancer immunotherapy.
• The presence of specific microbial antigens and their cross-reactivity with tumor antigens are biomarkers for predicting immunotherapy response.