Genome-wide CRISPR-Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1.
Animals
CRISPR-Cas Systems
Cytotoxicity, Immunologic
/ immunology
Genome-Wide Association Study
Histocompatibility Antigens Class I
/ immunology
Humans
Immunotherapy
/ methods
Lymphocyte Activation
/ immunology
Mice
Minor Histocompatibility Antigens
/ immunology
Neoplasms
/ immunology
Receptors, Antigen, T-Cell
/ immunology
T-Lymphocyte Subsets
/ immunology
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
15
02
2019
accepted:
10
12
2019
pubmed:
22
1
2020
medline:
14
4
2020
entrez:
22
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31959982
doi: 10.1038/s41590-019-0578-8
pii: 10.1038/s41590-019-0578-8
pmc: PMC6983325
mid: EMS85172
doi:
Substances chimiques
Histocompatibility Antigens Class I
0
MR1 protein, human
0
Minor Histocompatibility Antigens
0
Receptors, Antigen, T-Cell
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
178-185Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100327
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L008742/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : U54 DK110858
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : ErratumIn
Références
Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat. Immunol. 14, 908–916 (2013).
doi: 10.1038/ni.2665
Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).
doi: 10.1038/nature11605
Corbett, A. J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).
doi: 10.1038/nature13160
Gold, M. C. et al. MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. J. Exp. Med. 211, 1601–1610 (2014).
doi: 10.1084/jem.20140507
Eckle, S. B. G. et al. Recognition of vitamin B precursors and byproducts by mucosal associated invariant T cells. J. Biol. Chem. 290, 30204–30211 (2015).
doi: 10.1074/jbc.R115.685990
Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).
doi: 10.1038/ni.1890
Reantragoon, R. et al. Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor. J. Exp. Med. 209, 761–774 (2012).
doi: 10.1084/jem.20112095
Lepore, M. et al. Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire. Nat. Commun. 5, 3866 (2014).
doi: 10.1038/ncomms4866
Lepore, M. et al. Functionally diverse human T cells recognize non-microbial antigens presented by MR1. eLife 6, 1–22 (2017).
Gherardin, N. A. et al. Diversity of T cells restricted by the MHC class I-related molecule MR1 facilitates differential antigen recognition. Immunity 44, 32–45 (2016).
doi: 10.1016/j.immuni.2015.12.005
Keller, A. N. et al. Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. Nat. Immunol. 18, 402–411 (2017).
doi: 10.1038/ni.3679
Reantragoon, R. et al. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J. Exp. Med. 210, 2305–2320 (2013).
doi: 10.1084/jem.20130958
McWilliam, H. E. G. et al. The intracellular pathway for the presentation of vitamin B-related antigens by the antigen-presenting molecule MR1. Nat. Immunol. 17, 531–537 (2016).
doi: 10.1038/ni.3416
Lamichhane, R. & Ussher, J. E. Expression and trafficking of MHC related protein 1 (MR1). J. Immunol. 38, 42–49 (2017).
Young, M. H. et al. MAIT cell recognition of MR1 on bacterially infected and uninfected cells. PLoS ONE 8, e53789 (2013).
doi: 10.1371/journal.pone.0053789
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
doi: 10.1038/nm.3909
Gherardin, N. A. et al. Enumeration, functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma. Sci. Rep. 8, 4159 (2018).
doi: 10.1038/s41598-018-22130-1
Parra-Cuadrado, J. F. et al. A study on the polymorphism of human MHC class I-related MR1 gene and identification of an MR1-like pseudogene. Tissue Antigens 56, 170–172 (2000).
doi: 10.1034/j.1399-0039.2000.560211.x
Seshadri, C. et al. A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis. Genes Immun. 18, 8–14 (2017).
doi: 10.1038/gene.2016.41
Lion, J. et al. MR1B, a natural spliced isoform of the MHC-related 1 protein, is expressed as homodimers at the cell surface and activates MAIT cells. Eur. J. Immunol. 43, 1363–1373 (2013).
doi: 10.1002/eji.201242461
Shalem, O. et al. Genome-scale CRISPR–Cas9 knockout screening in human cells. Science 343, 84–87 (2014).
doi: 10.1126/science.1247005
Patel, S. J. et al. Identification of essential genes for cancer immunotherapy. Nature 548, 537–542 (2017).
doi: 10.1038/nature23477
Reith, W., LeibundGut-Landmann, S. & Waldburger, J.-M. Regulation of MHC class II gene expression by the class II transactivator. Nat. Rev. Immunol. 5, 793–806 (2005).
doi: 10.1038/nri1708
Laugel, B. et al. Engineering of isogenic cells deficient for MR1 with a CRISPR/Cas9 lentiviral system: tools to study microbial antigen processing and presentation to human MR1-restricted T cells. J. Immunol. 197, 971–982 (2016).
doi: 10.4049/jimmunol.1501402
Eckle, S. B. G. et al. A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. J. Exp. Med. 211, 1585–1600 (2014).
doi: 10.1084/jem.20140484
Alía, M., Ramos, S., Mateos, R., Bravo, L. & Goya, L. Response of the antioxidant defense system to tert-butyl hydroperoxide and hydrogen peroxide in a human hepatoma cell line (HepG2). J. Biochem. Mol. Toxicol. 19, 119–128 (2005).
doi: 10.1002/jbt.20061
Irvine, D. J., Purbhoo, M. A., Krogsgaard, M. & Davis, M. M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).
doi: 10.1038/nature01076
Hulin-Curtis, S. L. et al. Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus. Oncotarget 9, 26328–26341 (2018).
doi: 10.18632/oncotarget.25242
Wooldridge, L. et al. MHC class I molecules with superenhanced CD8 binding properties bypass the requirement for cognate TCR recognition and nonspecifically activate CTLs. J. Immunol. 184, 3357–3366 (2010).
doi: 10.4049/jimmunol.0902398
Lissina, A. et al. Protein kinase inhibitors substantially improve the physical detection of T-cells with peptide-MHC tetramers. J. Immunol. Methods 340, 11–24 (2009).
doi: 10.1016/j.jim.2008.09.014
Tungatt, K. et al. Antibody stabilization of peptide-MHC multimers reveals functional T cells bearing extremely low-affinity TCRs. J. Immunol. 194, 463–474 (2014).
doi: 10.4049/jimmunol.1401785
Betts, M. R. et al. Sensitive and viable identification of antigen-specific CD8
doi: 10.1016/S0022-1759(03)00265-5
Haney, D. et al. Isolation of viable antigen-specific CD8
doi: 10.1016/j.jim.2011.04.003
Ryan, M. D., King, A. M. Q. & Thomas, G. P. Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J. Gen. Virol. 72, 2727–2732 (1991).
doi: 10.1099/0022-1317-72-11-2727
Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014).
doi: 10.1038/nmeth.3047
Li, W. et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 15, 554 (2014).
doi: 10.1186/s13059-014-0554-4
Maciocia, P. M. et al. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat. Med. 23, 1416–1423 (2017).
doi: 10.1038/nm.4444