Targeting cancer: tumor-specific splicing events give rise to immunogenic, tumor-wide neoantigens

In a recent study published in Nature,¹ Kwok et al. identified tumor-wide antigens that derived from tumor-specific splicing events, known as neojunctions (NJs) (Fig. 1a). The study identified two distinct neopeptide-encoding NJs (NEJs) that were spatially and temporally conserved in glioblastoma (GBM) patients and induced an HLA-dependent T cell response. The discovery of these NEJs, as well as the pipeline used for their identification, harbors significant potential for the development of tumor vaccines and adoptive cell therapies that might be effective across various cancer entities.

Fig. 1

a Schematic overview of an example for a neojunction. b–g Work process that led to the discovery of public, tumor-wide, NJ-derived immunogenic neoantigens. b shows the 12 tumors that were investigated from the TCGA data sets. GBM glioblastoma, LGG low-grade glioma, MESO mesothelioma, LUAD lung adenocarcinoma, LIHC liver hepatocellular carcinoma, STAD stomach adenocarcinoma, KIRP kidney renal papillary cell carcinoma, LUSC lung squamous cell carcinoma, COAD colon adenocarcinoma, KICH Kidney chromophobe, PRAD Prostate adenocarcinoma, SKCM skin cutaneous melanoma. c Investigation of spatial distribution of public NJs was done by analyzing existing data sets and acquiring 10 spatially separated biopsies from 51 glioma patients. d Temporal conversation was investigated in data sets of recurring tumors and metastases. e NJ expression and HLA presentation were investigated using pre-existing MS data sets and bioinformatical prediction. f NJs that were public, tumor-wide, expressed and temporally conserved were selected for immunogenicity. g Induction of immunity by NEJs was confirmed with APC-based T cell activation and subsequent tumor cell killing by NEJ-targeting T cells. The figure was created with Biorender

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