Li Guangyuan, Guzmán-Bringas Omar U, Sharma Aman, Dellacherie Maxence, Sekhri Palak, Yamin Rachel, Stepec Dejan, Burq Maximilien, Clotea Ioana, Tardio Ethan, Natarajan Aswin, Harpaz Zachary, Liu Xinya, Requena David, Taylor Darren, Ueberheide Beatrix M, Krogsgaard Michelle, Cruz C Russell Y, Cimermancic Peter, Yarmarkovich Mark
Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
bioRxiv. 2025 Jul 7:2025.01.22.634237. doi: 10.1101/2025.01.22.634237.
T-cell-based immunotherapies have revolutionized cancer treatment, yet only a minority of patients are eligible for these approaches, significantly constrained by the limited knowledge of tumor-specific antigens. Here we present ImmunoVerse, a comprehensive map of T cell targets across 21 cancer types, revealing actionable tumor-specific targets in 89% of tumors analyzed. To define the repertoire of actionable T cell targets, we conducted an exhaustive pan-cancer analysis, integrating data from 7,188 RNA-Seq, 1,771 immunopeptidomes from 512 biological samples and 208 single-cell cancer datasets using novel AI methods, and compared these against 17,384 normal samples covering 51 tissues. Our analysis uncovered 62 viable surface protein targets and 28,446 tumor-specific HLA-presented antigens, deriving from 11 distinct molecular events, across 21 tumor types. Among these, we identified 5,928 previously uncharacterized neoantigens, new tumor self-antigens, peptides derived from tumor-specific cryptic ORFs, tumor-associated microbial targets and a novel splicing-derived PMEL peptide (sPMEL) with enhanced abundance and safety compared to the canonical clinical targets. We successfully expanded sPMEL-specific T cells, validating the therapeutic potential of these targets in functional assays. We highlight 153 promising new tumor targets and experimentally validate 19 targets representing six antigen classes. In addition to being the most comprehensive atlas of targets in scope, ImmunoVerse offers the most extensively annotated resource with key parameters for target selection, providing critical insights for therapeutic prioritization and clinical translation. To catalyze therapeutic development, we released our pan-cancer target atlas through an interactive web portal (https://www.immuno-verse.com) and made the accompanying toolkits available to the scientific community. This work redefines the landscape of therapeutic T cell targets and provides a foundational resource to unlock immunotherapy development across multiple cancers previously considered intractable.
基于T细胞的免疫疗法彻底改变了癌症治疗方式，但只有少数患者适合这些方法，这受到肿瘤特异性抗原知识有限的严重限制。在此，我们展示了ImmunoVerse，这是一张涵盖21种癌症类型的T细胞靶点综合图谱，揭示了在89%的分析肿瘤中可采取行动的肿瘤特异性靶点。为了定义可采取行动的T细胞靶点库，我们进行了详尽的泛癌分析，使用新颖的人工智能方法整合了来自7188个RNA测序、512个生物样本的1771个免疫肽组和208个单细胞癌症数据集的数据，并将这些数据与涵盖51个组织的17384个正常样本进行比较。我们的分析在21种肿瘤类型中发现了62个可行的表面蛋白靶点和28446个肿瘤特异性HLA呈递抗原，这些抗原源自11种不同的分子事件。其中，我们鉴定出5928个以前未表征的新抗原、新的肿瘤自身抗原、源自肿瘤特异性隐秘开放阅读框的肽、肿瘤相关微生物靶点以及一种新型剪接衍生的PMEL肽（sPMEL），与典型临床靶点相比，其丰度和安全性更高。我们成功扩增了sPMEL特异性T细胞，在功能试验中验证了这些靶点的治疗潜力。我们重点介绍了153个有前景的新肿瘤靶点，并通过实验验证了代表六种抗原类别的19个靶点。除了是范围最全面的靶点图谱外，ImmunoVerse还提供了注释最广泛的资源，包含靶点选择的关键参数，为治疗优先级排序和临床转化提供了关键见解。为了推动治疗开发，我们通过交互式网络门户（https://www.immuno-verse.com）发布了我们的泛癌靶点图谱，并向科学界提供了配套工具包。这项工作重新定义了治疗性T细胞靶点的格局，并提供了一个基础资源，以开启针对多种以前被认为难以治疗的癌症的免疫疗法开发。
