IMMU-06. Landscape of adaptive immunity of childhood brain cancers. (3rd June 2022)

• Record Type: Journal Article
• Authors: Raphael, Itay; Chikina, Maria; Broniscer, Alberto; Pollack, Ian; Rajasundaram, Dhivyaa; Kohanbash, Gary
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 1
• Page Start: i82
• Page End: i82
• Publication Date: 2022-06-03
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac079.299
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: T lymphocytes have a unique ability to recognize a vast array of antigens prompted by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) is key to understand MHC-restricted anti-tumor immunity and for developing T cell-centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNA-Seq data from 997 pediatric brain tumor patients and performed a large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the entire spectrum of pediatric brain tumors. We show that the relative ratio between T cell diversity (clonality) and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis both within and between tumor types. Interestingly, we show that CEI was strongly associated with molecular subgroups of medulloblastoma but not with known tumor-genomic features of these subgroups. Investigation of TCR clones recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals 9 TCR clusters which are tumor type restricted with defined prognoses and HLA dominance. Using computational immunogenomics and machine learning-based investigations of these clusters yielded novel putative HLA-restricted tumor antigens which could bind and activate the clusters' specific TCRs. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell-centered immunotherapies. These findings have major implications for understanding the interplay between T cell and tumor genomic, and for developing new immunotherapies for children with brain tumors.