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Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Michael D. Crowther
  • Garry Dolton
  • Mateusz Legut
  • Marine E. Caillaud
  • Angharad Lloyd
  • Meriem Attaf
  • Sarah A.E. Galloway
  • Cristina Rius
  • Colin P. Farrell
  • Barbara Szomolay
  • Ann Ager
  • Alan L. Parker
  • Anna Fuller
  • Donia, Marco
  • James McCluskey
  • Jamie Rossjohn
  • Svane, Inge Marie
  • John D. Phillips
  • Andrew K. Sewell

Human leukocyte antigen (HLA)-independent, T cell–mediated targeting of cancer cells would allow immune destruction of malignancies in all individuals. Here, we use genome-wide CRISPR–Cas9 screening to establish that a T cell receptor (TCR) recognized and killed most human cancer types via the monomorphic MHC class I-related protein, MR1, while remaining inert to noncancerous cells. Unlike mucosal-associated invariant T cells, recognition of target cells by the TCR was independent of bacterial loading. Furthermore, concentration-dependent addition of vitamin B-related metabolite ligands of MR1 reduced TCR recognition of cancer cells, suggesting that recognition occurred via sensing of the cancer metabolome. An MR1-restricted T cell clone mediated in vivo regression of leukemia and conferred enhanced survival of NSG mice. TCR transfer to T cells of patients enabled killing of autologous and nonautologous melanoma. These findings offer opportunities for HLA-independent, pan-cancer, pan-population immunotherapies.

OriginalsprogEngelsk
TidsskriftNature Immunology
Vol/bind21
Udgave nummer2
Sider (fra-til)178-185
Antal sider8
ISSN1529-2908
DOI
StatusUdgivet - 2020

ID: 235774868