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in Vaccine-Induced Antitumor Immunity Versus Adoptive Immunotherapy1
,
,
*
Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center;
Department of Biochemistry and Molecular Biology, Oregon Graduate Institute; and
Department of Molecular Microbiology and Immunology and
Oregon Cancer Center, Oregon Health Sciences University, Portland, OR 97213
The mechanism by which tumors are rejected following the adoptive
transfer of tumor-specific T cells is not well characterized. Recent
work has challenged the requirement for cytotoxicity mediated by either
the perforin/granzyme or Fas/Fas ligand pathway in T cell-mediated
tumor regression. Many reports, including ours, suggest that
tumor-specific production of IFN-
is critical for T cell-mediated
tumor regression. However, in most of these studies the evidence to
support the role for IFN- is only indirect. We have directly
examined the requirement for IFN- using IFN- knockout (GKO) mice.
The results show an interesting dichotomy in the requirement for
IFN-: Antitumor immunity induced by active-specific immunotherapy
(vaccination) required IFN-, whereas adoptive immunotherapy did not.
In GKO mice vaccination with the GM-CSF gene-modified B16BL6-D5 tumor
(D5-G6) failed to induce protective immunity against parental D5 tumor.
However, adoptive transfer of effector T cells from GKO mice cured
100% of GKO mice with established pulmonary metastases and induced
long term antitumor immunity and depigmentation of skin. Furthermore,
in vivo neutralization of IFN- by mAb treatment or adoptive transfer
into IFN- receptor knockout mice failed to block the therapeutic
efficacy of effector T cells generated from wild-type or perforin
knockout mice. Analysis of regressing metastases revealed similar
infiltrates of macrophages and granulocytes in both wild-type and GKO
mice. These results indicate that in this adoptive immunotherapy model,
neither a direct effect on the tumor nor an indirect effect of IFN-
through activation of myeloid or lymphoid cells is critical for
therapeutic efficacy.
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