CrossDome: an interactive R package to predict cross-reactivity risk using immunopeptidomics databases.

Area of Science:

• Immunology
• Bioinformatics
• Computational Biology

Background:

• T-cell immunotherapies offer targeted cancer treatment but face safety concerns due to potential off-target toxicity.
• Molecular mimicry can lead to T-cell cross-reactivity, where engineered T-cells attack healthy tissues, causing severe adverse events.
• Predicting and mitigating off-target toxicity is crucial for developing safer immunotherapy products.

Purpose of the Study:

• To introduce CrossDome, a multi-omics suite designed to predict the risk of off-target toxicity in T-cell-based immunotherapies.
• To evaluate the efficacy of CrossDome using known cross-reactivity cases and experimentally validated data.
• To provide a computational tool for enhancing the safety profile of immunotherapies.

Main Methods:

• Developed CrossDome, a suite with peptide-centered and TCR-centered prediction protocols.
• Utilized a multi-omics approach integrating expression data, HLA binding, and immunogenicity predictions.
• Validated the tool on 16 known cross-reactivity cases and an extended dataset of experimentally determined cross-reactive peptides.

Main Results:

• CrossDome accurately predicted known off-target peptides, including the TITIN-derived peptide associated with lethal damage (99+ percentile rank).
• The TCR-centered approach, incorporating a contact map penalty system, improved prediction accuracy compared to the peptide-centered method.
• CrossDome achieved high enrichment rates for validated cross-reactive peptides (up to 82% for the TCR-centered protocol in the top 50 candidates).

Conclusions:

• CrossDome is an effective tool for predicting and mitigating off-target toxicity in T-cell immunotherapies.
• The TCR-centered prediction protocol demonstrates superior performance in identifying potential adverse reactions.
• This R package and web interface offer valuable support for antigen discovery pipelines and immunotherapy development, enhancing patient safety.