Hg-81novel and Shared Neoantigen for Glioma T Cell Therapy Derived From Histone 3 Variant H3.3 K27m Mutation
Year: 2016
Type: article
Abstract: Recent genetic studies have revealed that over 60% of midline gliomas, such as diffuse intrinsic pontine gliomas (DIPG), in children and young adults harbor the amino-acid substitution from lysine (K) to methionine (M) at the position 27 of H3.3. We evaluated whether H3.3-derived peptides that encompass the H3.3 K27M mutation can induce specific cytotoxic T lymphocyte (CTL) responses in human leukocyte antigen (HLA)-A2+ CD8+ T-cells. A synthetic peptide encompassing amino-acid positions around the H3.3 K27M mutation induced specific CTL lines which recognized not only the synthetic peptide loaded on T2 cells but also lysed HLA-A2+ DIPG cell lines which endogenously harbor the H3.3.K27M mutation. On the other hand, CTL lines did not react to HLA-A2 + , H3.3 K27M mutation-negative cells or HLA-A2-negative, H3.3 K27M mutation+ cells. Furthermore, CTL clones with high and specific affinities to HLA-A2-H3.3.K27M-tetramer were successfully obtained, and α- and β-chain cDNAs from a high-affinity T cell receptor (TCR) were cloned into a lentiviral vector. Human T-cells transduced with the TCR demonstrated antigen-specific activation, and alanine scanning demonstrated that the key amino-acid sequence motif in the epitope for the TCR reactivity is not shared by any known human protein. These data provide us with a strong basis for developing peptide-based vaccines as well as adoptive transfer therapy using autologous T-cells transduced with the TCR.
Source: Neuro-Oncology
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4234372204