Yingying Ma, Yangyang Cai, Jiaxin Yang, Zheng Zhao, Zefeng Chen, Dezhong Lv, Jiaxin Yu, Changbo Yang, Kefan Liu, Mengqian Zeng, Han Guo, Kang Xu, Qinghua Jiang, Hang Yin, Juan Xu, Yongsheng Li
The identification of tumor-derived neoantigens that elicit an immune response has led to significant advancements in cancer immunotherapy. We comprehensively investigated the neoantigen atlas in Chinese glioma patients via the integration of whole-exome sequencing, transcriptome, and ribosome profiling. We further proposed MINER (Multi-omics Integration for NEoantigen Recognition) to prioritize neoantigens that integrate HLA-I binding and the TCR response to increase accuracy. In particular, we emphasized the importance of non-canonical open reading frames in neoantigen generation and demonstrated that both gene fusions and somatic mutations contribute to the production of neoantigens complementally. We identified a novel subtype (neo_W) of IDH-wildtype glioma, which was characterized by a higher neoantigen burden and correlated with better survival outcomes. Finally, we experimentally validated therapeutic combinations of immune checkpoint inhibitors that target the RAS-RAF-MEK-ERK signaling pathway for treatment of neo_W glioma patients. Multi-omics-guided characterization of neoantigens provides valuable knowledge for precision therapy of glioma.