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A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease

Ding, Xilai ; Bian, Guanglin ; Leigh, Nicholas D LU orcid ; Qiu, Jingxin ; McCarthy, Philip L ; Liu, Hong ; Aygun-Sunar, Semra ; Burdelya, Lyudmila G ; Gudkov, Andrei V and Cao, Xuefang (2012) In Journal of immunology 189(10). p.27-4719
Abstract

Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and nonhematologic malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the effectiveness of the transplantation therapy. CBLB502 is a novel agonist for TLR5 derived from Salmonella flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of CBLB502 on GVT activity. Using two tumor models that do not express TLR5, and thereby do not directly respond to CBLB502, we found that CBLB502 treatment significantly enhanced allogeneic CD8(+) T cell-mediated GVT activity, which was evidenced by decreased tumor burden and improved... (More)

Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and nonhematologic malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the effectiveness of the transplantation therapy. CBLB502 is a novel agonist for TLR5 derived from Salmonella flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of CBLB502 on GVT activity. Using two tumor models that do not express TLR5, and thereby do not directly respond to CBLB502, we found that CBLB502 treatment significantly enhanced allogeneic CD8(+) T cell-mediated GVT activity, which was evidenced by decreased tumor burden and improved host survival. Importantly, histopathologic analyses showed that CBLB502 treatment did not exacerbate the moderate graft-versus-host disease condition caused by the allogeneic CD8(+) T cells. Moreover, mechanistic analyses showed that CBLB502 stimulates CD8(+) T cell proliferation and enhances their tumor killing activity mainly indirectly through a mechanism that involves the IL-12 signaling pathway and the CD11c(+) and CD11b(+) populations in the bone marrow cells. This study demonstrates a new beneficial effect of CBLB502, and suggests that TLR5-mediated immune modulation may be a promising approach to improve GVT immunity without exacerbating graft-versus-host disease.

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; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, CD8-Positive T-Lymphocytes/immunology, Cell Proliferation/drug effects, Flagellin/chemistry, Graft vs Host Disease/immunology, Graft vs Tumor Effect/drug effects, Hematopoietic Stem Cell Transplantation, Immunity, Cellular/drug effects, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, Neoplasms, Experimental/immunology, Salmonella/chemistry, Toll-Like Receptor 5/agonists, Transplantation, Homologous
in
Journal of immunology
volume
189
issue
10
pages
9 pages
publisher
American Association of Immunologists
external identifiers
  • pmid:23045613
  • scopus:84868588130
ISSN
1550-6606
DOI
10.4049/jimmunol.1201206
language
English
LU publication?
no
id
fc68c0a5-d1e3-4c0b-90df-b014fd12d8b4
date added to LUP
2020-04-30 23:24:15
date last changed
2024-04-03 06:59:16
@article{fc68c0a5-d1e3-4c0b-90df-b014fd12d8b4,
  abstract     = {{<p>Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and nonhematologic malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the effectiveness of the transplantation therapy. CBLB502 is a novel agonist for TLR5 derived from Salmonella flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of CBLB502 on GVT activity. Using two tumor models that do not express TLR5, and thereby do not directly respond to CBLB502, we found that CBLB502 treatment significantly enhanced allogeneic CD8(+) T cell-mediated GVT activity, which was evidenced by decreased tumor burden and improved host survival. Importantly, histopathologic analyses showed that CBLB502 treatment did not exacerbate the moderate graft-versus-host disease condition caused by the allogeneic CD8(+) T cells. Moreover, mechanistic analyses showed that CBLB502 stimulates CD8(+) T cell proliferation and enhances their tumor killing activity mainly indirectly through a mechanism that involves the IL-12 signaling pathway and the CD11c(+) and CD11b(+) populations in the bone marrow cells. This study demonstrates a new beneficial effect of CBLB502, and suggests that TLR5-mediated immune modulation may be a promising approach to improve GVT immunity without exacerbating graft-versus-host disease.</p>}},
  author       = {{Ding, Xilai and Bian, Guanglin and Leigh, Nicholas D and Qiu, Jingxin and McCarthy, Philip L and Liu, Hong and Aygun-Sunar, Semra and Burdelya, Lyudmila G and Gudkov, Andrei V and Cao, Xuefang}},
  issn         = {{1550-6606}},
  keywords     = {{Animals; CD8-Positive T-Lymphocytes/immunology; Cell Proliferation/drug effects; Flagellin/chemistry; Graft vs Host Disease/immunology; Graft vs Tumor Effect/drug effects; Hematopoietic Stem Cell Transplantation; Immunity, Cellular/drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasms, Experimental/immunology; Salmonella/chemistry; Toll-Like Receptor 5/agonists; Transplantation, Homologous}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{10}},
  pages        = {{27--4719}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology}},
  title        = {{A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1201206}},
  doi          = {{10.4049/jimmunol.1201206}},
  volume       = {{189}},
  year         = {{2012}},
}