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H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2(+) patients with diffuse midline glioma

Authors

  • L. Immisch
  • G. Papafotiou
  • O. Popp
  • P. Mertins
  • T. Blankenstein
  • G. Willimsky

Journal

  • Journal for ImmunoTherapy of Cancer

Citation

  • J Immunother Cancer 10 (10): e005535

Abstract

  • Diffuse midline glioma is the leading cause of solid cancer-related deaths in children with very limited treatment options. A majority of the tumors carry a point mutation in the histone 3 variant (H3.3) creating a potential HLA-A*02:01 binding epitope (H3.3K27M(26-35)). Here, we isolated an H3.3K27M-specific T cell receptor (TCR) from transgenic mice expressing a diverse human TCR repertoire. Despite a high functional avidity of H3.3K27M-specific T cells, we were not able to achieve recognition of cells naturally expressing the H3.3K27M mutation, even when overexpressed as a transgene. Similar results were obtained with T cells expressing the published TCR 1H5 against the same epitope. CRISPR/Cas9 editing was used to exclude interference by endogenous TCRs in donor T cells. Overall, our data provide strong evidence that the H3.3K27M mutation is not a suitable target for cancer immunotherapy, most likely due to insufficient epitope processing and/or amount to be recognized by HLA-A*02:01 restricted CD8(+) T cells.


DOI

doi:10.1136/jitc-2022-005535