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Neoantigen-targeted CD8 + T cell responses with PD-1 blockade therapy.

Cristina Puig-SausBarbara SenninoSongming PengClifford L WangZheng PanBenjamin YuenBhamini PurandareDuo AnBoi B QuachDiana NguyenHuiming XiaSameeha JilaniKevin ShaoClaire McHughJohn GreerPhillip PeabodySaparya NayakJonathan HooverSara SaidKyle JacobyOlivier DalmasSusan P FoyAndrew ConroyMichael C YiChristine ShiehWilliam LuKatharine HeeringaYan MaShahab ChizariMelissa J PillingMarc TingRamya TunuguntlaSalemiz SandovalRobert MootTheresa HunterSidi ZhaoJustin D SacoIvan Perez-GarcilazoEgmidio MedinaAgustin Vega-CrespoIgnacio Baselga-CarreteroGabriel Abril-RodriguezGrace CherryDeborah J WongJasreet HundalBartosz ChmielowskiDaniel E SpeiserMichael T BethuneXiaoyan R BaoAlena GrosMalachi GriffithMalachi GriffithJames R HeathAlex FranzusoffStefanie J MandlAntoni Ribas
Published in: Nature (2023)
Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells 1-14 . The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we applied recently developed technologies 15-17 to capture neoantigen-specific T cells from blood and tumours from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. We generated personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T cell receptors (neoTCRs). Multiple T cells with different neoTCR sequences (T cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These neoTCR clonotypes were recurrently detected over time in the blood and tumour. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T cell responses in the blood and tumour to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoTCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Thus, effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8 + T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.
Keyphrases
  • crispr cas
  • single cell
  • endothelial cells
  • sars cov
  • cancer therapy
  • newly diagnosed
  • dendritic cells
  • regulatory t cells
  • drug delivery
  • bone marrow
  • peripheral blood
  • induced pluripotent stem cells