title: Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity.
abstract: Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.
authors.affiliation: Department of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. GhoshA1@mskcc.org
authors.forename: Arnab
authors.initials: A
authors.lastname: Ghosh
authors.forename: Yildirim
authors.initials: Y
authors.lastname: Dogan
authors.forename: Maxim
authors.initials: M
authors.lastname: Moroz
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Holland
authors.forename: Nury L
authors.initials: NL
authors.lastname: Yim
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Rao
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.forename: Daniel
authors.initials: D
authors.lastname: Tannenbaum
authors.forename: Durva
authors.initials: D
authors.lastname: Masih
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tsai
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.forename: Olaf
authors.initials: O
authors.lastname: Penack
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hanash
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: Kelly
authors.initials: K
authors.lastname: Piersanti
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: M Lia
authors.initials: ML
authors.lastname: Palomba
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sauer
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse