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Immunology |
The Medical School [K. A. C.], Cell and Molecular Biology Program [J. C. M.], and Departments of Surgery [K. A. C., K. S., J. A. F., J. J. M.], Pathology [R. K.], and Internal Medicine [B. G. R., J. J. M.], University of Michigan Medical Center, Ann Arbor, Michigan 48103; Extramural Research, Immunex Corporation, Seattle, Washington 98101 [E. K. T.], and the Department of Pathology, Oncology Institute, Loyola University Medical Center, Maywood, Illinois 60153 [B. J. N.]
Dendritic cells (DCs) can efficiently acquire foreign antigen(s)
from apoptotic cells and induce MHC class I-restricted,
antigen-specific CTLs. An accumulation of DCs within solid tumor masses
in situ has been associated indirectly with a more
favorable prognosis. Therefore, DCs may offer an efficient means for
triggering immune responses within tumors, particularly in those masses
containing significant apoptosis. We examined whether delivery of DCs
could, alone, impact on the progressive growth of a tumor with a
relatively high apoptotic index. We detected significant early
apoptosis within the mass of a s.c. growing murine MT-901 breast
carcinoma. DCs could efficiently engulf MT-901 tumor apoptotic cells
in vitro. Intratumoral injections of syngeneic but not
allogeneic DCs resulted in significant inhibition of MT-901 tumor
growth. Histological examination of the tumor revealed intense
mononuclear cell infiltration during and after DC injections. Tumor
growth inhibition was relatively radiosensitive and dependent on
host-derived CD8+ T cells. The baseline level of tumor
apoptosis could be increased substantially by tumor necrosis
factor 
administration, leading to a greater DC-mediated antitumor
effect. The antitumor effect could also be enhanced by first pulsing
DCs with the foreign helper protein, keyhole limpet hemocyanin, prior
to intratumoral delivery and combining it with the systemic
administration of interleukin 2. Splenocytes from treated animals
showed heightened levels of specific CTL activity and production of
cytokines. The level of in situ tumor apoptosis appears
to play a critical role in DC-mediated antitumor effects. The potential
implication of these findings in DC-based tumor therapy strategies is
discussed.
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