PMID- 32755564
OWN - NLM
STAT- MEDLINE
DCOM- 20210914
LR  - 20240330
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 28
IP  - 12
DP  - 2020 Dec 2
TI  - A Distinct Transcriptional Program in Human CAR T Cells Bearing the 4-1BB 
      Signaling Domain Revealed by scRNA-Seq.
PG  - 2577-2592
LID - S1525-0016(20)30374-9 [pii]
LID - 10.1016/j.ymthe.2020.07.023 [doi]
AB  - T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 
      have produced impressive outcomes for the treatment of B cell malignancies, but 
      different products vary in kinetics, persistence, and toxicity profiles based on 
      the co-stimulatory domains included in the CAR. In this study, we performed 
      transcriptional profiling of bulk CAR T cell populations and single cells to 
      characterize the transcriptional states of human T cells transduced with CD3zeta, 
      4-1BB-CD3zeta (BBzeta), or CD28-CD3zeta (28zeta) co-stimulatory domains at rest and after 
      activation by triggering their CAR or their endogenous T cell receptor (TCR). We 
      identified a transcriptional signature common across CARs with the CD3zeta signaling 
      domain, as well as a distinct program associated with the 4-1BB co-stimulatory 
      domain at rest and after activation. CAR T cells bearing BBzeta had increased 
      expression of human leukocyte antigen (HLA) class II genes, ENPP2, and 
      interleukin (IL)-21 axis genes, and decreased PD1 compared to 28zeta CAR T cells. 
      Similar to previous studies, we also found BBzeta CAR CD8 T cells to be enriched in 
      a central memory cell phenotype and fatty acid metabolism genes. Our data 
      uncovered transcriptional signatures related to costimulatory domains and 
      demonstrated that signaling domains included in CARs uniquely shape the 
      transcriptional programs of T cells.
CI  - Copyright (c) 2020 The American Society of Gene and Cell Therapy. Published by 
      Elsevier Inc. All rights reserved.
FAU - Boroughs, Angela C
AU  - Boroughs AC
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
FAU - Larson, Rebecca C
AU  - Larson RC
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
FAU - Marjanovic, Nemanja D
AU  - Marjanovic ND
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Gosik, Kirk
AU  - Gosik K
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Castano, Ana P
AU  - Castano AP
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA.
FAU - Porter, Caroline B M
AU  - Porter CBM
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Lorrey, Selena J
AU  - Lorrey SJ
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA.
FAU - Ashenberg, Orr
AU  - Ashenberg O
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Jerby, Livnat
AU  - Jerby L
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Hofree, Matan
AU  - Hofree M
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Smith-Rosario, Gabriela
AU  - Smith-Rosario G
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Morris, Robert
AU  - Morris R
AD  - Howard Hughes Medical Institute, Koch Institute of Integrative Cancer Research, 
      Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 
      02140, USA.
FAU - Gould, Joshua
AU  - Gould J
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Riley, Lauren S
AU  - Riley LS
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA.
FAU - Berger, Trisha R
AU  - Berger TR
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA.
FAU - Riesenfeld, Samantha J
AU  - Riesenfeld SJ
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Rozenblatt-Rosen, Orit
AU  - Rozenblatt-Rosen O
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA.
FAU - Choi, Bryan D
AU  - Choi BD
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA.
FAU - Regev, Aviv
AU  - Regev A
AD  - Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA; Howard Hughes Medical Institute, Koch Institute of Integrative Cancer 
      Research, Department of Biology, Massachusetts Institute of Technology, 
      Cambridge, MA 02140, USA. Electronic address: aregev@broadinstitute.org.
FAU - Maus, Marcela V
AU  - Maus MV
AD  - Cellular Immunotherapy Program and Cancer Center, Massachusetts General Hospital, 
      Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; 
      Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 
      02139, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 
      02114, USA. Electronic address: mvmaus@mgh.harvard.edu.
LA  - eng
GR  - K08 CA166039/CA/NCI NIH HHS/United States
GR  - R01 CA238268/CA/NCI NIH HHS/United States
GR  - T32 AI007529/AI/NIAID NIH HHS/United States
GR  - T32 AI118692/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200725
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (4-1BB Ligand)
RN  - 0 (RNA, Small Cytoplasmic)
RN  - 0 (Receptors, Chimeric Antigen)
SB  - IM
MH  - 4-1BB Ligand/*chemistry/*metabolism
MH  - Cell Engineering/*methods
MH  - HEK293 Cells
MH  - Humans
MH  - K562 Cells
MH  - Protein Domains/*genetics
MH  - RNA, Small Cytoplasmic/*genetics
MH  - RNA-Seq/methods
MH  - Receptors, Chimeric Antigen/*genetics
MH  - Signal Transduction/*genetics
MH  - Single-Cell Analysis
MH  - T-Lymphocytes/*metabolism
MH  - *Transcriptome
MH  - Transduction, Genetic
PMC - PMC7704462
OTO - NOTNLM
OT  - CAR T cells
OT  - T cell activation
OT  - adoptive cellular therapy
OT  - single-cell RNA sequencing
OT  - transcriptional profiling
EDAT- 2020/08/07 06:00
MHDA- 2021/09/15 06:00
PMCR- 2021/12/02
CRDT- 2020/08/07 06:00
PHST- 2020/04/28 00:00 [received]
PHST- 2020/06/26 00:00 [revised]
PHST- 2020/07/21 00:00 [accepted]
PHST- 2020/08/07 06:00 [pubmed]
PHST- 2021/09/15 06:00 [medline]
PHST- 2020/08/07 06:00 [entrez]
PHST- 2021/12/02 00:00 [pmc-release]
AID - S1525-0016(20)30374-9 [pii]
AID - 10.1016/j.ymthe.2020.07.023 [doi]
PST - ppublish
SO  - Mol Ther. 2020 Dec 2;28(12):2577-2592. doi: 10.1016/j.ymthe.2020.07.023. Epub 
      2020 Jul 25.