TY - JOUR
T1 - A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease
AU - Ding, Xilai
AU - Bian, Guanglin
AU - Leigh, Nicholas D
AU - Qiu, Jingxin
AU - McCarthy, Philip L
AU - Liu, Hong
AU - Aygun-Sunar, Semra
AU - Burdelya, Lyudmila G
AU - Gudkov, Andrei V
AU - Cao, Xuefang
PY - 2012/11/15
Y1 - 2012/11/15
N2 - 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.
AB - 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.
KW - Animals
KW - CD8-Positive T-Lymphocytes/immunology
KW - Cell Proliferation/drug effects
KW - Flagellin/chemistry
KW - Graft vs Host Disease/immunology
KW - Graft vs Tumor Effect/drug effects
KW - Hematopoietic Stem Cell Transplantation
KW - Immunity, Cellular/drug effects
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred DBA
KW - Neoplasms, Experimental/immunology
KW - Salmonella/chemistry
KW - Toll-Like Receptor 5/agonists
KW - Transplantation, Homologous
U2 - 10.4049/jimmunol.1201206
DO - 10.4049/jimmunol.1201206
M3 - Article
C2 - 23045613
SN - 1550-6606
VL - 189
SP - 4719
EP - 4727
JO - Journal of immunology
JF - Journal of immunology
IS - 10
ER -