Immune checkpoint inhibition (ICI) is clinically active against multiple cancers, including urothelial cancer at the non-muscle invasive, muscle-invasive, and metastatic stages. Despite this, large numbers of patients experience disease progression and relapse after treatment with ICI-containing regimens. Tumor antigen-specific T cells are critical to ICI response, however few studies have evaluated the breadth and magnitude of tumor antigen-specific T cell responses with ICI therapy. In this study, we mapped the tumor antigen immunodominance hierarchy in the BBN963 model of murine basal-like bladder cancer for endogenous tumor neoantigens expressed physiologically. We used a high-throughput matrixed ELISpot assay to detect CD8+ T cell responses to predicted BBN963 tumor antigens derived from multiple mutational genomic sources. We found CD8+ T cell responses were directed against a subset of tumor antigens forming a stable and reproducible immunodominance hierarchy across individual mice. Treatment with anti-PD-1 or anti-CTLA-4 did not substantially reshape this hierarchy or broadly shift dominant responses to previously defined subdominant epitopes. Predicted binding stability and mass spectrometry validation were associated with antigen immunogenicity. Cancer-testis antigens, endogenous retroviral antigens, and SNV-derived tumor antigens that were immunogenic were found across tumor subclones. By diversifying the immunogenic antigen repertoire beyond SNVs, we achieved nearly 100% tumor subclone coverage, suggesting that broader antigen selection could help immunotherapy target more tumor subclones. In conclusion, this study supports the stability of the immunodominance hierarchy under ICI therapy and a role for broadening antigen discovery to multiple expressional sources in immunotherapy design.
Fini, M., Alley, J. R., Vensko, S. P., Karthikeyan, D., Lee, J. S., Paul, E., Jaeger, A., Kim, W., Vincent, B.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 14
- Comments 0