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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 ; Tang, Youzhou ; Capitano, Maegan L ; Qiu, Jingxin ; McCarthy, Philip L ; Liu, Hong and Cao, Xuefang (2013) In Journal of immunology (Baltimore, Md. : 1950) 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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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 (Baltimore, Md. : 1950)
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
2020-05-04 09:09:09
@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},
  language     = {eng},
  month        = {02},
  number       = {3},
  pages        = {50--1341},
  publisher    = {American Association of Immunologists},
  series       = {Journal of immunology (Baltimore, Md. : 1950)},
  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},
}