title: CD40 ligand promotes priming of fully potent antitumor CD4(+) T cells in draining lymph nodes in the presence of apoptotic tumor cells.
abstract: The presence or absence of CD4(+) T cell help can determine the direction of adaptive immune responses toward either cross-priming or cross-tolerance. It has been demonstrated that interactions of CD40-CD40 ligand can replace CD4(+) T cell help and enable dendritic cells to prime cytotoxic T cells. Here, we demonstrate that antitumor reactivity induced in regional lymph nodes (LNs) by s.c. injection of CD40 ligand (CD40L)-transduced tumor (MCA205 CD40L) showed far superior therapeutic efficacy against established brain tumors of a weakly immunogenic fibrosarcoma, MCA205, when adoptively transferred. Coinjection of apoptotic, but not necrotic parental tumor cells with CD40L-expressing tumor cells caused a strong synergistic induction of antitumor reactivity in tumor-draining LNs. Freshly isolated T cells from LNs immunized with apoptotic parental tumor cells and MCA205 CD40L were capable of mediating regression of the parental tumor in vivo. In contrast, T cells derived from LNs immunized without MCA205 CD40L required ex vivo anti-CD3/IL-2 activation to elicit therapeutic activity. On anti-CD3/IL-2 activation, cells from LNs immunized with MCA205 CD40L exhibited superior per cell antitumor reactivity. An in vitro depletion study revealed that either CD4(+) or CD8(+) T cells could mediate therapeutic efficacy but that the antitumor efficacy mediated by CD4(+) T cells was far superior. Cytosolic flow cytometric analyses indicated that priming of CD4(+) cells in LNs draining CD40L-expressing tumors was polarized to the Th1 type. This is the first report that fully potent antitumor CD4(+) T cell priming was promoted by s.c. injection of CD40L-transduced tumor in the presence of apoptotic tumor cells.
authors.affiliation: Department of Medicine (II), Niigata University Medical School, Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: H
authors.initials: H
authors.lastname: Kagamu
authors.forename: H
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: K
authors.initials: K
authors.lastname: Itoh
authors.forename: H
authors.initials: H
authors.lastname: Kuriyama
authors.forename: N
authors.initials: N
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Ishiguro
authors.forename: J
authors.initials: J
authors.lastname: Tanaka
authors.forename: E
authors.initials: E
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Hamada
authors.forename: F
authors.initials: F
authors.lastname: Gejyo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D019496:Cancer Vaccines; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000096:biosynthesis; D019041:L-Selectin / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D019041:L-Selectin; D023201:CD40 Ligand