Shared H3.3 K27M mutation is recognized as a neoantigen by specific TCRs and leads to aberrant IFN-γ production and upregulation of PD-L1 on glioma cells

Identification: 4032


Description

Shared H3.3 K27M mutation is recognized as a neoantigen by specific TCRs and leads to aberrant IFN-γ production and upregulation of PD-L1 on glioma cells

Zinal Chheda1, Gary Kohanbash1, John Sidney2, Kaori Okada1, Shruti Shrivastav1, Diego Carrera1, Shuming Liu1, Naznin Jahan1, Sabine Mueller1, Angel M. Carcaboso3, Alessandro Sette2, Yafei Hou1 and Hideho Okada1*

1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA; 2Center for Infectious Disease; Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA; 3Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Esplugues de Llobregat, Spain

Brain cancers are the leading cause of cancer related mortality in children. Approximately 70% of diffuse intrinsic pontine gliomas (DIPG) and other midline gliomas harbor the amino-acid substitution from lysine (K) to methionine (M) at the position 27 of H3.3 (H3.3.K27M mutation). In vitro stimulation of HLA-A2+ CD8+ T-cells with a synthetic peptide encompassing the H3.3.K27M mutation (H3.3.K27M epitope) induced cytotoxic T lymphocyte (CTL) lines which lysed HLA-A2+, H3.3.K27M-mutated DIPG cell lines. The H3.3.K27M epitope peptide indicated an excellent affinity (Kd 151 nM) to HLA-A2. From CTL clones with high and specific affinities to HLA-A2-H3.3.K27M-tetramer, cDNAs for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector. Human HLA-A2+ T-cells transduced with the TCR demonstrated antigen-specific reactivity as well as anti-glioma responses both in vitro and in vivo intracranial glioma xenografts. Furthermore, 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. Interestingly, H3.3.K27M-mutated glioma cells produce IFN-γ and show upregulated PD-L1 likely due to demethylation at H3.3.K27M. These data provide us with a strong basis for developing adoptive transfer therapy using autologous T-cells transduced with the H3.3.K27M-specific TCR.

Funding: R01NS096954 (Okada), Parker Institute for Cancer Immunotherapy, V Foundation, UCSF Resource Allocation Program

Credits

Credits: None available.

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