Tumor-wide RNA Splicing Aberrations Generate Immunogenic Public Neoantigens

T-cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens. 1 However, their efficacy is often limited in tumors with fewer somatic mutations and significant intratumoral heterogeneity, such as glioblastoma. 2–5 Here we introduce a previously uncharacterized class of tumor-wide and public neoantigens, originating from RNA-splicing aberrations in various cancer types. Notably, we identified T-cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22 . In multi-site-directed biopsies across various cancer types, we detected the tumor-wide expression of the GNAS neojunction within glioma, mesothelioma, prostate cancer, and liver cancer patients. Importantly, these neoantigens were proven to be endogenously generated and presented by tumor cells under physiological conditions, which was sufficient in triggering the eradication of cancer cells by neoantigen-specific CD8+ T-cells. Moreover, our study unravels the complex interplay of dysregulated splicing factor expression in specific cancer subtypes, which leads to recurrent patterns of neojunction upregulation. These findings offer a robust molecular basis for T-cell-based immunotherapy that targets a newfound class of tumor-wide public neoantigens, addressing the challenges of intratumoral heterogeneity. By characterizing this unique class of tumor-wide and public neoantigens, our research emphasizes the need to consider intratumoral heterogeneity in the quest for effective cancer immunotherapies. These findings have significant implications for the development of targeted treatments and mark a pivotal step in the ongoing journey to uncover neoantigens for cancer immunotherapy.