|
|
Development of Systemic Immunity to Glioblastoma Multiforme Using Tumor
Cells Genetically Engineered to Express the Membrane-Associated Isoform of
Macrophage Colony-Stimulating Factor
Martin R. Graf, Martin R. Jadus, John C.
Hiserodt, H. Terry Wepsic and Gale A. Granger
Departments of Molecular Biology and Biochemistry
[MRG,
GAG] and Pathology, University of California, Irvine, CA 92697 [MRJ, JCH, HTW];
and The Veterans Affairs Medical Center, Long Beach, CA 90822 [MRJ, HTW].
Address correspondence and reprint requests to Dr. Martin R. Graf at
the current address: Department of Anatomy, Virginia Commonwealth
University, P.O. Box 709, 1101 East Marshall Street, Richmond, VA
23298.
We investigated the ability of Fischer rat T9 glioblastoma cells transduced
with cDNA genes for the secreted (s) or membrane-associated (m) isoform
of M-CSF to elicit an antitumor response when implanted into syngeneic
animals.
Intracranial (i.c.) implantation of 1 x 105
T9 cells expressing mM-CSF (T9/mM-CSF) resulted in 80% tumor rejection.
Electron microscopy of the T9/mM-CSF tumor site, 2–4 days
postimplantation, showed marked infiltration by macrophages, many of
which were in physical contact with the T9/mM-CSF cells.
Animals that
rejected T9/mM-CSF cells were resistant to i.c. rechallenge with T9
cells, but not syngeneic MadB106 breast adenocarcinoma cells,
suggesting that T9-specific immunity can be generated within the
brain via the endogenous APCs.
Intracranial injection of parental T9,
vector control (T9/LXSN), or T9 cells secreting M-CSF (T9/sM-CSF) was
100% fatal.
Subcutaneous injection of 1 x
107 T9/sM-CSF, T9/LXSN, or parental T9 cells resulted in
progressive tumors.
In contrast, T9/mM-CSF cells injected s.c. were
destroyed in 7–10 days and animals developed systemic immunity to
parental T9 cells.
Passive transfer of CD3+ T cells from
the spleens of immune rats into naive recipients transferred T9
glioma-specific immunity.
In vitro, splenocytes from T9/mM-CSF-immunized
rats specifically proliferated in response to various syngeneic
glioma stimulator cells.
However, only marginal T cell-mediated
cytotoxicity was observed by these splenocytes in a CTL assay against
T9 target cells, regardless of restimulation with T9 cells.
Subcutaneous immunization with viable T9/mM-CSF cells was effective
in eradicating i.c. T9 tumors.
Copyright © 1999 by The American Association of
Immunologists
|
