TY - JOUR
T1 - A Distinct Transcriptional Program in Human CAR T Cells Bearing the 4-1BB Signaling Domain Revealed by scRNA-Seq
AU - Boroughs, Angela C.
AU - Larson, Rebecca C.
AU - Marjanovic, Nemanja D.
AU - Gosik, Kirk
AU - Castano, Ana P.
AU - Porter, Caroline B.M.
AU - Lorrey, Selena J.
AU - Ashenberg, Orr
AU - Jerby, Livnat
AU - Hofree, Matan
AU - Smith-Rosario, Gabriela
AU - Morris, Robert
AU - Gould, Joshua
AU - Riley, Lauren S.
AU - Berger, Trisha R.
AU - Riesenfeld, Samantha J.
AU - Rozenblatt-Rosen, Orit
AU - Choi, Bryan D.
AU - Regev, Aviv
AU - Maus, Marcela V.
N1 - Publisher Copyright:
© 2020 The American Society of Gene and Cell Therapy
PY - 2020/12/2
Y1 - 2020/12/2
N2 - 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 CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) 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 CD3ζ 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 BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ 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. Maus, Regev, and colleagues performed a deep transcriptional analysis of CAR T cells bearing different signaling domains, at rest and after activation. Findings include CAR-specific signatures and a distinct program activated in CARs with 4-1BB domains that was characterized by expression of central memory markers, MHC class II, and IL-21, among others.
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 CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) 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 CD3ζ 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 BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ 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. Maus, Regev, and colleagues performed a deep transcriptional analysis of CAR T cells bearing different signaling domains, at rest and after activation. Findings include CAR-specific signatures and a distinct program activated in CARs with 4-1BB domains that was characterized by expression of central memory markers, MHC class II, and IL-21, among others.
KW - CAR T cells
KW - T cell activation
KW - adoptive cellular therapy
KW - single-cell RNA sequencing
KW - transcriptional profiling
UR - http://www.scopus.com/inward/record.url?scp=85088996471&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2020.07.023
DO - 10.1016/j.ymthe.2020.07.023
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C2 - 32755564
AN - SCOPUS:85088996471
SN - 1525-0016
VL - 28
SP - 2577
EP - 2592
JO - Molecular Therapy
JF - Molecular Therapy
IS - 12
ER -