Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
02 09 2022
02 09 2022
Historique:
received:
12
11
2021
revised:
18
05
2022
accepted:
27
06
2022
pubmed:
7
7
2022
medline:
9
9
2022
entrez:
6
7
2022
Statut:
ppublish
Résumé
Current chimeric antigen receptor-modified (CAR) T-cell products are evaluated in bulk, without assessing functional heterogeneity. We therefore generated a comprehensive single-cell gene expression and T-cell receptor (TCR) sequencing data set using pre- and postinfusion CD19-CAR T cells from blood and bone marrow samples of pediatric patients with B-cell acute lymphoblastic leukemia. We identified cytotoxic postinfusion cells with identical TCRs to a subset of preinfusion CAR T cells. These effector precursor cells exhibited a unique transcriptional profile compared with other preinfusion cells, corresponding to an unexpected surface phenotype (TIGIT+, CD62Llo, CD27-). Upon stimulation, these cells showed functional superiority and decreased expression of the exhaustion-associated transcription factor TOX. Collectively, these results demonstrate diverse effector potentials within preinfusion CAR T-cell products, which can be exploited for therapeutic applications. Furthermore, we provide an integrative experimental and analytic framework for elucidating the mechanisms underlying effector development in CAR T-cell products. Utilizing clonal trajectories to define transcriptional potential, we find a unique signature of CAR T-cell effector precursors present in preinfusion cell products. Functional assessment of cells with this signature indicated early effector potential and resistance to exhaustion, consistent with postinfusion cellular patterns observed in patients. This article is highlighted in the In This Issue feature, p. 2007.
Identifiants
pubmed: 35792801
pii: 705276
doi: 10.1158/2159-8290.CD-21-1508
pmc: PMC9437573
mid: NIHMS1821587
doi:
Substances chimiques
Antigens, CD19
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2098-2119Subventions
Organisme : NIAID NIH HHS
ID : U01 AI150747
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136514
Pays : United States
Organisme : NIAID NIH HHS
ID : F32 AI157296
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
Références
Sci Transl Med. 2014 Feb 19;6(224):224ra25
pubmed: 24553386
Trends Immunol. 2019 Dec;40(12):1149-1162
pubmed: 31734149
Cell. 2021 Dec 9;184(25):6081-6100.e26
pubmed: 34861191
Cell. 2011 Jan 21;144(2):296-309
pubmed: 21241896
Nat Biotechnol. 2018 Jun;36(5):421-427
pubmed: 29608177
Cell Rep. 2017 Oct 3;21(1):17-26
pubmed: 28978471
Cancer Discov. 2022 Aug 5;12(8):1886-1903
pubmed: 35554512
Cancer Cell. 2014 Dec 8;26(6):923-937
pubmed: 25465800
Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):5980-5
pubmed: 24711416
Exp Mol Med. 2021 Feb;53(2):202-209
pubmed: 33627794
Cell. 1988 Dec 2;55(5):917-24
pubmed: 3142692
Nat Immunol. 2011 Jun;12(6):492-9
pubmed: 21739672
Science. 2003 Nov 7;302(5647):1041-3
pubmed: 14605368
Nat Immunol. 2019 Feb;20(2):163-172
pubmed: 30643263
J Immunol. 2005 Nov 1;175(9):5895-903
pubmed: 16237082
N Engl J Med. 2014 Oct 16;371(16):1507-17
pubmed: 25317870
Lancet. 2015 Feb 7;385(9967):517-528
pubmed: 25319501
Philos Trans R Soc Lond B Biol Sci. 2015 Aug 19;370(1675):
pubmed: 26150657
Cell. 2019 Feb 7;176(4):775-789.e18
pubmed: 30595452
Nat Med. 2017 Jan 6;23(1):18-27
pubmed: 28060797
Nature. 1988 Dec 15;336(6200):692-5
pubmed: 3143919
Nat Methods. 2017 Mar;14(3):309-315
pubmed: 28114287
Nat Immunol. 2009 Jan;10(1):48-57
pubmed: 19011627
Genes Dev. 2000 Apr 15;14(8):913-26
pubmed: 10783164
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Nature. 2017 Mar 2;543(7643):113-117
pubmed: 28225754
Cancer Discov. 2021 Sep;11(9):2186-2199
pubmed: 33820778
Nat Methods. 2015 May;12(5):380-1
pubmed: 25924071
Immunity. 2015 Feb 17;42(2):265-278
pubmed: 25680272
J Immunol. 2020 Aug 15;205(4):901-906
pubmed: 32669309
PLoS Negl Trop Dis. 2020 Jun 23;14(6):e0008414
pubmed: 32574175
Nat Methods. 2017 Nov;14(11):1083-1086
pubmed: 28991892
PLoS Comput Biol. 2015 Nov 25;11(11):e1004503
pubmed: 26606115
Nat Immunol. 2020 Dec;21(12):1552-1562
pubmed: 33046887
Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129-57
pubmed: 1751545
Nat Rev Genet. 2012 Mar 13;13(4):227-32
pubmed: 22411467
Immunity. 2009 Aug 21;31(2):178-80
pubmed: 19699168
Nat Commun. 2020 Jan 10;11(1):219
pubmed: 31924795
Leukemia. 2004 Apr;18(4):676-84
pubmed: 14961035
Eur J Immunol. 2005 Sep;35(9):2608-16
pubmed: 16106370
J Immunol. 2015 Jun 15;194(12):6155-63
pubmed: 25957172
Nat Med. 2018 May;24(5):563-571
pubmed: 29713085
Nat Cell Biol. 2002 May;4(5):E131-6
pubmed: 11988758
Nat Rev Immunol. 2015 Aug;15(8):486-99
pubmed: 26205583
Nature. 2019 Dec;576(7786):293-300
pubmed: 31802004
Leukemia. 2015 Feb;29(2):387-95
pubmed: 24888271
Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):13139-44
pubmed: 25157137
Blood Adv. 2022 Apr 21;:
pubmed: 35446934
N Engl J Med. 2018 Feb 1;378(5):449-459
pubmed: 29385376
Mol Ther. 2021 Feb 3;29(2):645-657
pubmed: 33278564
Cell. 1988 Nov 4;55(3):395-7
pubmed: 3141060
J Clin Invest. 2019 Mar 12;129(5):2123-2132
pubmed: 30860496
Elife. 2020 Mar 18;9:
pubmed: 32187010
Nat Immunol. 2020 Oct;21(10):1205-1218
pubmed: 32839608
Mol Ther. 2020 Dec 2;28(12):2577-2592
pubmed: 32755564
Front Immunol. 2020 Feb 14;11:206
pubmed: 32117317
Nat Methods. 2014 Jun;11(6):653-5
pubmed: 24793455