Abstract PO2-24-12: Tumor-specific circRNAs elicit anti-tumor immune response via encoding cryptic antigenic peptides

Abstract Emerging data have shown that previously defined noncoding genomes might encode human leukocyte antigen (HLA) binding peptides as cryptic antigens to stimulate adaptive immunity. However, the significance and mechanisms of cryptic antigens in anti-tumor immunity remain unclear. Here, mass spectrometry for HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I binding cryptic antigenic peptides, which were noncanonically translated by a tumor-specific circular RNA CEIP (circCEIP). Importantly, the cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and elicited anti-tumor immunity. Clinically, the expression of circCEIP and its encoding peptides was associated with massive infiltration of antigen-specific CD8+ T cells and better survival of breast cancer and melanoma patients. Mechanistically, circCEIP-encoding peptides had strong binding affinity to both HLA-I and II molecules, respectively. In vivo, administration of vaccines devised by tumor-specific circRNA or its encoding peptides in breast cancer or melanoma-bearing mice dramatically enhanced the infiltration of tumor-antigen specific cytotoxic T cells, leading to effective tumor control. Overall, our findings revealed that noncanonical translation of circRNAs can drive efficient anti-tumor immunity, suggesting that vaccination exploiting tumor-specific circRNAs may serve as an appealing immunotherapeutic strategy against malignant tumors. Citation Format: Di Huang, Jianing Chen, Shicheng Su, Erwei Song. Tumor-specific circRNAs elicit anti-tumor immune response via encoding cryptic antigenic peptides [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-24-12.