Mapping T cell infiltration patterns in glioma tumor tissue

ABSTRACT Background The glioma immune repertoire has emerged as a vital point of interest, particularly in the context of immunotherapeutics development and as a key player for prognostic and diagnostic biomarker identification. Methods Tumor tissue was collected from glioma patients and targeted immune repertoire sequencing of tumor infiltrating lymphocytes (TIL) from each of the four collected glioma tumor subtypes was performed. Gliomas were stratified based on WHO21 classification to map the TCR landscape of astrocytomas (grade II/III, grade IV), glioblastomas, and oligodendrogliomas. Results Following stratification of TCR repertoires and complete clonotype, V-J cassette, and CDR3 analysis, we identified cohort-specific levels of diversity, clonotype sharing, and conservation. Partitioning of these repertoires based on TCR diversity revealed significant influence on patient survival. Furthermore, mapping of CDR3 binding regions to antigens and their origins highlighted prognostic biomarkers and identified sequences binding to viral signatures associated with patient clinical outcomes. Conclusion These findings underscore the importance of characterizing TCR repertoires in the context of the patient clinical condition. These unique repertoire signatures and correlated antigens may facilitate patient outcome prognostication and serve as a potential foundation for immunotherapeutic applications. Key Points Glioma subtypes can be differentiated via TCR repertoire characterization. T cell diversity in gliomas influences patient overall survival. TCR Clonotypes are binding sites for prognostic tumor proteins and viral disease. Importance of the Study In this study, we characterized the infiltrating immune repertoire of glial tumors through targeted T cell receptor sequencing of four glioma subtypes: grade II/III astrocytomas, grade IV astrocytomas, glioblastoma, and oligodendrogliomas. We performed multi-level analyses to examine TCR repertoire diversity across these subtypes, identifying unique clonotype prevalence and region usage in alpha-beta T cells. Classification of clonotypes relative to known associated antigen databases revealed unique signatures related to the viral diseases of cytomegalovirus and Epstein-Barr virus, as well as clonotypes with binding affinity for human tumor-derived proteins prognostic for glioma. This study reveals a unique perspective into the differentiation of glioma subtypes based on TCR clonotypes and further solidifies the role of TCR mapping in the patient care paradigm.