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Granzyme B-mediated damage of CD8+ T cells impairs graft-versus-tumor effect

Bian, Guanglin ; Ding, Xilai ; Leigh, Nicholas D LU orcid ; Tang, Youzhou ; Capitano, Maegan L ; Qiu, Jingxin ; McCarthy, Philip L ; Liu, Hong and Cao, Xuefang (2013) In Journal of immunology 190(3). p.50-1341
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,... (More)

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.

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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Apoptosis/immunology, Bone Marrow Transplantation/adverse effects, CD8-Positive T-Lymphocytes/immunology, Cell Division, Cell Line, Tumor/transplantation, Fas Ligand Protein/biosynthesis, Graft vs Host Disease/etiology, Graft vs Tumor Effect/physiology, Granzymes/deficiency, Immunologic Memory, Interferon-gamma/biosynthesis, Lymphocyte Activation, Lymphoma/immunology, Mice, Mice, Inbred Strains, Radiation Chimera, Tumor Burden
in
Journal of immunology
volume
190
issue
3
pages
50 - 1341
publisher
American Association of Immunologists
external identifiers
  • pmid:23264653
  • scopus:84872702952
ISSN
1550-6606
DOI
10.4049/jimmunol.1201554
language
English
LU publication?
no
id
4cba32b7-5d09-4a93-81b0-d0484a87010d
date added to LUP
2020-04-30 23:23:11
date last changed
2024-06-13 17:03:41
@article{4cba32b7-5d09-4a93-81b0-d0484a87010d,
  abstract     = {{<p>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.</p>}},
  author       = {{Bian, Guanglin and Ding, Xilai and Leigh, Nicholas D and Tang, Youzhou and Capitano, Maegan L and Qiu, Jingxin and McCarthy, Philip L and Liu, Hong and Cao, Xuefang}},
  issn         = {{1550-6606}},
  keywords     = {{Animals; Apoptosis/immunology; Bone Marrow Transplantation/adverse effects; CD8-Positive T-Lymphocytes/immunology; Cell Division; Cell Line, Tumor/transplantation; Fas Ligand Protein/biosynthesis; Graft vs Host Disease/etiology; Graft vs Tumor Effect/physiology; Granzymes/deficiency; Immunologic Memory; Interferon-gamma/biosynthesis; Lymphocyte Activation; Lymphoma/immunology; Mice; Mice, Inbred Strains; Radiation Chimera; Tumor Burden}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{3}},
  pages        = {{50--1341}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology}},
  title        = {{Granzyme B-mediated damage of CD8+ T cells impairs graft-versus-tumor effect}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1201554}},
  doi          = {{10.4049/jimmunol.1201554}},
  volume       = {{190}},
  year         = {{2013}},
}