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Dependent1
* Department of Biological Sciences, University of Maryland, Baltimore, MD 21250; and
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Mice deficient for the STAT6 gene (STAT6-/- mice)
have enhanced immunosurveillance against primary and metastatic tumors.
Because STAT6 is a downstream effector of the IL-4R, and IL-13 binds to
the type 2 IL-4R, IL-13 has been proposed as an inhibitor that blocks
differentiation of tumor-specific CD8+ T cells. Immunity in
STAT6-/- mice is unusually effective in that 45–80% of
STAT6-/- mice with established, spontaneous metastatic
4T1 mammary carcinoma, whose primary tumors are surgically excised,
survive indefinitely, as compared with <10% of STAT+/+
(BALB/c) mice. Surprisingly, STAT6-/- and BALB/c
reciprocal bone marrow chimeras do not have increased
immunosurveillance, demonstrating that immunity requires
STAT6-/- hemopoietic and nonhemopoietic components.
Likewise, CD1-/- mice that are NKT deficient and
therefore IL-13 deficient also have heightened tumor immunity. However,
STAT6-/- and CD1-/- reciprocal bone marrow
chimeras do not have increased survival, suggesting that immunity in
STAT6-/- and CD1-/- mice is via
noncomplementing mechanisms. Metastatic disease is not reduced in
BALB/c mice treated with an IL-13 inhibitor, indicating that IL-13
alone is insufficient for negative regulation of 4T1 immunity.
Likewise, in vivo depletion of CD4+CD25+ T
cells in BALB/c mice does not increase survival, demonstrating that
CD4+CD25+ cells do not regulate immunity.
Cytokine production and tumor challenges into
STAT6-/-IFN-
-/- mice indicate that
IFN- is essential for immunity. Therefore, immunosurveillance in
STAT6-/- mice facilitates survival against metastatic
cancer via an IFN--dependent mechanism involving hemopoietic and
nonhemopoietic derived cells, and is not exclusively dependent on
counteracting IL-13 or CD4+CD25+ T
cells.
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