title: A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease.
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 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.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Xilai
authors.initials: X
authors.lastname: Ding
authors.forename: Guanglin
authors.initials: G
authors.lastname: Bian
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Leigh
authors.forename: Jingxin
authors.initials: J
authors.lastname: Qiu
authors.forename: Philip L
authors.initials: PL
authors.lastname: McCarthy
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Semra
authors.initials: S
authors.lastname: Aygun-Sunar
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Burdelya
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005408:Flagellin / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D020350:Graft vs Tumor Effect / Q000187:drug effects* / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012475:Salmonella / Q000737:chemistry*; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D051198:Toll-Like Receptor 5; D005408:Flagellin