Granzyme B-mediated damage of CD8+ T cells impairs graft-versus-tumor effect
(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
- Bian, Guanglin ; Ding, Xilai ; Leigh, Nicholas D LU ; Tang, Youzhou ; Capitano, Maegan L ; Qiu, Jingxin ; McCarthy, Philip L ; Liu, Hong and Cao, Xuefang
- publishing date
- 2013-02-01
- 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
- 2024-06-26 15:58:05
@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}}, }