title: Comparison of naïve and central memory derived CD8+effector cell engraftment fitness and function following adoptive transfer.
abstract: Human CD8+effector T cells derived from CD45RO+CD62L+precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO+CD62L-precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8+effector T cells derived from CD45RA+CD62L+precursors enriched for naïve and stem cell memory precursors (TN/SCM) with that of TCM. We found that cytotoxic T cells (CTLs) derived from TCMtranscribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from TN/SCM. Higher frequencies of CTLs derived from TCMretained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/ScidIL-2RγCnullmice, CD8+TCMderived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8+TCMderived CD19CAR+CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8+TN/SCMderived counterparts. These studies support the use of TCMenriched cell products for adoptive therapy of cancer.
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: ChingLam W
authors.initials: CW
authors.lastname: Wong
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Urak
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Taus
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Aguilar
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Armen
authors.initials: A
authors.lastname: Mardiros
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Lihua E
authors.initials: LE
authors.lastname: Budde
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Berger
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
keywords: Antitumor activity; adoptive therapy; central memory T cell derived CTLs; engraftment fitness; naïve T cell derived CTLs