Thursday, April 3, 2025
4/3/2025
Pancancer discovery and exploration of shared splicing neoantigens - PROJECT SUMMARY Cellular and immunotherapies are increasingly emerging as front-line treatments in clinical oncology. However, current immune checkpoint blockade therapies improve outcome in only a subset of patients for a few cancers. While immunotherapy is typically reserved for cancer patients with a high mutational burden, neoantigens produced from post-transcriptional regulation provide an untapped reservoir of common immunogenic targets for new targeted cancer therapies. To identify and exploit alternative mRNAs for the design of shared therapies, our team of computational and cancer biologists developed an innovative workflow to define and experimentally validate diverse forms of splicing neoantigens (Science Translational Medicine 2024). Our computational workflow, called Splicing Neoantigen Finder (SNAF), employs innovative artificial intelligence approaches to accurately predict shared immunogenic splicing neoantigens that can serve as the basis for broadly used immunotherapies. In addition to MHC presented neoantigens, SNAF defines novel expressed cell surface full- length neo-peptides from long-read sequencing data. Our computational and experimental studies demonstrate the feasibility of highly shared splicing neoantigens as targets for therapy in multiple solid and hematological malignancies, find shared neoantigens that span diverse malignancies, nominate new mechanisms underlying their regulation (splicing failure) and suggest a subset of antigens specifically derive from the tumor microenvironment. To capitalize on these new findings, we propose to create a comprehensive splicing neoantigen atlas of 30 adult and pediatric malignancies that span both known and novel disease subtypes. This work will establish clear roles for splicing neoantigen burden and the tumor microenvironment across cancers, define key molecular and extrinsic regulators (e.g., viral infection), and nominate recurrent liabilities for future vaccine and immunotherapy development. These analyses are expected to reveal thousands of highly shared splicing neoantigens, derived from distinct regulatory mechanisms, that are both specific to and recurrent across malignancies. To interactively explore and interrogate this pancancer splicing neoantigen atlas, we will develop an advanced web portal called NeoXplorer. NeoXplorer will build upon our recently developed and intuitive pancancer splicing analysis web infrastructure, to facilitate comparative cancer and healthy tissue analyses of splicing neoantigens, clinical and genetic covariates, orthogonal genomics and long-read sequencing evidence, advanced visualizations of protein structure and neoantigen immunogenicity and putative splicing regulators. The proposed atlas and tools will establish a crucial knowledgebase and interfaces to define highly shared and recurrent therapeutic targets that will have long-lasting impact on the field of cancer biology.
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