The Immunopeptidomic Landscape of Ependymomas provide actionable antigens for T cell-based immunotherapy

Ependymoma (EPN) are primary tumors of the nervous system. Due to their growth pattern, most ependymoma can be managed with neurosurgical resection alone. A substantial proportion of these tumors recurs or display infiltrative growth pattern, however. Therapeutic options after neurosurgical resection are limited. Based on tumor board recommendations, radiation therapy will be recommended for some patients. Systemic treatment options for progressive ependymoma include platin-based therapeutic regimes or a combination of lapatinib and temozolomide. Peptide-based immunotherapy represents a promising low-side effect therapeutic option relying on the induction of tumor-specific T cells targeting human leukocyte antigens (HLA)-presented peptides. We here analyzed the landscape of naturally presented HLA class I and II ligands of primary ependymomas using a comparative mass-spectrometry-based immunopeptidomic approach to delineate naturally presented ependymoma-associated antigens. We discovered a subset of EPN-exclusive peptides including HLA-A*02 and HLA-A*25/HLA-A*26–restricted HLA ligands and identified a small panel of cancer/testis antigens (CTAs)-derived HLA ligands. Furthermore, we outlined immunopeptidomic alterations in different EPN-subgroups and progressive EPNs and performed subsequent functional characterization for demonstrating immunogenicity in vitro. Taken together, we provide actionable targets that could further be explored as a T-cell based immunotherapeutic strategy in this tumor entity.