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,
*
University of California, Los Angeles, Medical School-Wadsworth Pulmonary Laboratory, Veterans Administration West Los Angeles Healthcare Center,
Jonsson Comprehensive Cancer Center, and
Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, Medical School, Los Angeles, CA 90073
Secondary lymphoid tissue chemokine (SLC, also referred to as
Exodus 2 or 6Ckine) is a recently identified high endothelial-derived
CC chemokine. The ability of SLC to chemoattract both Th1 lymphocytes
and dendritic cells formed the rationale to evaluate this chemokine in
cancer immunotherapy. Intratumoral injection of recombinant SLC
evidenced potent antitumor responses and led to complete tumor
eradication in 40% of treated mice. SLC-mediated antitumor responses
were lymphocyte dependent as evidenced by the fact that this therapy
did not alter tumor growth in SCID mice. Studies performed in CD4 and
CD8 knockout mice also revealed a requirement for both CD4 and CD8
lymphocyte subsets for SLC-mediated tumor regression. In
immunocompetent mice, intratumoral SLC injection led to a significant
increase in CD4 and CD8 T lymphocytes and dendritic cells, infiltrating
both the tumor and the draining lymph nodes. These cell infiltrates
were accompanied by the enhanced elaboration of Th1 cytokines and
chemokines monokine induced by IFN-
and IFN--inducible protein 10
but a concomitant decrease in immunosuppressive cytokines at the tumor
site. In response to irradiated autologous tumor, splenic and lymph
node-derived cells from SLC-treated tumor-bearing mice secreted
significantly more IFN-, GM-CSF, and IL-12 and reduced levels of
IL-10 than did diluent-treated tumor-bearing mice. After stimulation
with irradiated autologous tumor, lymph node-derived lymphocytes from
SLC-treated tumor-bearing mice demonstrated enhanced cytolytic
capacity, suggesting the generation of systemic immune responses. These
findings provide a strong rationale for further evaluation of SLC in
tumor immunity and its use in cancer
immunotherapy.
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