title: Granzyme B-mediated damage of CD8+ T cells impairs graft-versus-tumor effect.
abstract: Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and other malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the treatment. Using multiple tumor models and diverse donor-host combinations, we have studied the role of granzyme B (GzmB) in GVT effect. We first confirmed previous findings that GzmB deficiency diminished the ability of a high dose of CD8(+) T cells to cause lethal graft-versus-host disease. However, when GVT studies were performed using a moderate cell dose that the hosts could tolerate, GzmB(-/-) CD8(+) T cells demonstrated a significantly enhanced GVT effect. GzmB-mediated, activation-induced cell death in wild-type CD8(+) T cells was found responsible for their reduced GVT activity. Conversely, GzmB(-/-) CD8(+) T cells exhibited enhanced expansion, skewed toward an effector or effector memory phenotype, and produced higher amounts of IFN-γ and Fas ligand that might contribute to GzmB-independent tumor control. These findings demonstrate for the first time, to our knowledge, that GzmB-mediated damage of CD8(+) T cells impairs the desired GVT effect. This study suggests that inhibiting donor-derived GzmB function may represent a promising strategy to improve GVT effect without exacerbating graft-versus-host disease.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Bian
authors.forename: Xilai
authors.initials: X
authors.lastname: Ding
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Leigh
authors.forename: Youzhou
authors.initials: Y
authors.lastname: Tang
authors.forename: Maegan L
authors.initials: ML
authors.lastname: Capitano
authors.forename: Jingxin
authors.initials: J
authors.lastname: Qiu
authors.forename: Philip L
authors.initials: PL
authors.lastname: McCarthy
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D045744:Cell Line, Tumor / Q000637:transplantation; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D020350:Graft vs Tumor Effect / Q000502:physiology*; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000601:surgery; D051379:Mice; D008815:Mice, Inbred Strains; D011828:Radiation Chimera; D047368:Tumor Burden
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse