title: CD154 inhibits tumor-induced apoptosis in dendritic cells and tumor growth.
abstract: We have recently demonstrated that murine and human tumors induce apoptosis of dendritic cells (DC). Here, we evaluated the effect of CD40 ligation on the survival of tumor-associated DC and tumor growth. Retroviral transduction of MC38 colon carcinoma cells with the CD154 gene resulted in inhibition of tumor growth. This effect was abrogated in IL-12 knockout mice. Immunohistochemical analysis revealed an increase in CD11c+ (N418) and CD8+ but not NLDC-145+ cells in CD154-transfected tumors in wild-type mice. This increase was less pronounced in IL-12-deficient mice. In vitro, overexpression of CD154 on tumor cells significantly decreased the level of tumor-induced DC apoptosis. Surprisingly, the CD154-induced protection of DC from tumor-induced apoptosis was IL-12 independent in vitro, suggesting an IL-12-dependent and an IL-12-independent mechanism of CD154-induced anti-tumor immunity. Thus, our data suggest a new strategy to improve immunotherapy of cancer by protecting DC from tumor-induced apoptosis.
authors.affiliation: Biologic Therapeutics Program, University of Pittsburgh Cancer Institute, PA 15213, USA.
authors.forename: C
authors.initials: C
authors.lastname: Esche
authors.forename: A
authors.initials: A
authors.lastname: Gambotto
authors.forename: Y
authors.initials: Y
authors.lastname: Satoh
authors.forename: V
authors.initials: V
authors.lastname: Gerein
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
authors.forename: S C
authors.initials: SC
authors.lastname: Watkins
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
authors.forename: M R
authors.initials: MR
authors.lastname: Shurin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007167:Immunotherapy; D016167:Integrin alphaXbeta2 / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014161:Transduction, Genetic
chemical_list: D016167:Integrin alphaXbeta2; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12