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,§,
,§
*
Laboratory of Molecular and Tumor Immunology, The Robert W. Franz Cancer Research Center, The Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213; and
Biochemistry and Molecular Biology, Oregon Graduate Institute, and
Department of Molecular Microbiology and Immunology and
§
Oregon Cancer Center, Oregon Health Sciences University, Portland, OR 97201
Vaccination with a poorly immunogenic/nonimmunogenic tumor fails to
protect the host from a subsequent challenge with the same tumor. The
mechanisms underlying the failure of these tumors to sensitize
therapeutic T cells are not clearly understood, but the inability of
host T cells to recognize tumor has been implicated. In this study,
vaccination with the poorly immunogenic B16BL6-D5 (D5 H-2b)
tumor fails to generate therapeutic T cells from the tumor
vaccine-draining lymph nodes (TVDLN) in our adoptive immunotherapy
model. However, if vaccination is performed with an allogeneic MHC
class I gene (H-2 Kd)-modified tumor, the T cells obtained
from the TVDLN are therapeutic after activation with anti-CD3 and
IL-2. Lymph nodes (LN) draining both D5 and D5-Kd tumor
vaccines contained increased numbers of cells with reduced expression
of L-selectin (L-selectinlow/-) compared with naive LN.
This implies that vaccination led to sensitization of T cells even in
LN draining the unmodified D5 tumor. L-selectinlow/- cells
from D5-Kd, but not D5, TVDLN were therapeutic in our
animal model. No antitumor activity was seen in the high level
L-selectin T cells. L-selectinlow/- T cells exhibited
tumor-specific cytokine release that was type 2 (IL-4, IL-10) following
vaccination with native D5 and type 1 (IFN-
) following vaccination
with gene-modified D5-Kd. Our data suggest that the failure
of unmodified D5 to generate therapeutic T cells is not due to an
inability to recognize tumor Ags, but, rather, to the induction of an
immune response that is ineffective in mediating tumor regression,
i.e., immune deviation.
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