CD154 inhibits tumor-induced apoptosis in dendritic cells and tumor growth.
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.
Esche
C
C
Biologic Therapeutics Program, University of Pittsburgh Cancer Institute, PA 15213, USA.
Gambotto
A
A
Satoh
Y
Y
Gerein
V
V
Robbins
P D
PD
Watkins
S C
SC
Lotze
M T
MT
Shurin
M R
MR
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
D016167:Integrin alphaXbeta2; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12