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CD8 + T cell targeting of tumor antigens presented by HLA-E.

Ravi F IyerMarieke C VerweijSujit S NairDavid W MorrowMandana MansouriDimple ChakravartyTeresa BeechwoodChristine MeyerLuke UebelhoerElvin J LauronAndrea N SelsethNessy JohnTin Htwe ThinSiarhei DzedzikColin Havenar-DaughtonMichael K AxthelmJanet DouglasAlan J KormanNina BhardwajAshutosh K TewariScott G HansenDaniel MalouliLouis J PickerKlaus Früh
Published in: Science advances (2024)
The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8 + T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8 + T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E + prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8 + T cell-based immunotherapies.
Keyphrases
  • nk cells
  • dendritic cells
  • poor prognosis
  • sars cov
  • prostate cancer
  • squamous cell carcinoma
  • cancer therapy
  • immune response
  • papillary thyroid
  • long non coding rna
  • squamous cell
  • protein kinase