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Pipeline to identify neoantigens exposed by radiation
Claire Lhuillier1, Samantha J Van Nest1, Nils-Petter Rudqvist2
1Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, United States.
Abstract:
Mutation-associated neoantigens are key targets of tumor-specific T cells and thus play a major role in driving responses to immune checkpoint blockade (ICB) therapy in tumors with high mutational burden. However, only a small number of mutated peptides are actually presented by MHC molecules and only a minority can induce T cell responses. In addition, the recognition of these neoantigens by T cells is limited by the level of expression of the mutated gene product in the tumor cells. Preclinical studies have shown that radiation can convert the irradiated tumor into an in situ vaccine, leading to the priming of tumor-specific T cells and to the rejection of otherwise ICB-resistant tumors. There is now preclinical and clinical evidence that radiation can upregulate the expression of genes containing immunogenic mutations and expose them to the immune system. Therefore, the identification of neoantigens upregulated by radiation could help to predict which patients might benefit from treatment with combinations of radiotherapy and ICB and could also be incorporated into personalized neoantigen vaccination strategies. In this chapter, we present the pipeline that we used to identify relevant radiation-upregulated neoantigens in a poorly immunogenic mouse model of metastatic breast cancer.
Insights
Radiation therapy can enhance the effectiveness of cancer immunotherapies by upregulating tumor neoantigens. Identifying these radiation-induced neoantigens may guide personalized treatment strategies combining radiotherapy and immune checkpoint blockade.
Area of Science:
- Oncology
- Immunology
- Radiation Oncology
Background:
- Mutation-associated neoantigens are crucial for T cell responses and immune checkpoint blockade (ICB) therapy efficacy.
- However, neoantigen presentation and T cell recognition are often limited by low expression and presentation levels.
- Radiation therapy shows potential to convert tumors into in situ vaccines, enhancing anti-tumor immunity.
Purpose of the Study:
- To identify neoantigens that are upregulated by radiation.
- To explore the potential of these radiation-upregulated neoantigens in predicting patient response to combined radiotherapy and ICB.
- To develop personalized neoantigen vaccination strategies.
Main Methods:
- Development of a computational pipeline to identify radiation-upregulated neoantigens.
- Application of the pipeline in a preclinical mouse model of metastatic breast cancer.
- Analysis of gene expression changes and neoantigen presentation following radiation treatment.
Main Results:
- Identification of specific neoantigens upregulated by radiation in the studied model.
- Demonstration that radiation can enhance the presentation of immunogenic mutations.
- Establishment of a method to discover radiation-responsive neoantigens.
Conclusions:
- Radiation therapy can increase the pool of targetable neoantigens, potentially overcoming resistance to ICB.
- Identifying radiation-upregulated neoantigens is critical for selecting patients for combined modality treatments.
- This approach could pave the way for novel personalized cancer vaccine strategies.
