Cutting Edge: STAT6-Deficient Mice Have Enhanced Tumor Immunity to Primary and Metastatic Mammary Carcinoma

Abstract

STAT4 and STAT6 are essential for the development of CD4+ Th1 and Th2 development, respectively. Tumor immunologists have hypothesized that Th1 cells are critical in tumor immunity because they facilitate differentiation of CD8+ T cells, which are potent anti-tumor effectors. We have used STAT4−/− and STAT6−/− mice to test this hypothesis. BALB/c and knockout mice were challenged in the mammary gland with the highly malignant and spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma. Primary tumor growth and metastatic disease are reduced in STAT6−/− mice relative to BALB/c and STAT4−/− mice. Ab depletions demonstrate that the effect is mediated by CD8+ T cells, and immunized STAT6−/− mice have higher levels of 4T1-specific CTL than BALB/c or STAT4−/− mice. Surprisingly, Th1 or Th2 cells are not involved, because CD4 depletion does not diminish the anti-tumor effect. Therefore, deletion of the STAT6 gene facilitates development of potent anti-tumor immunity via a CD4+-independent pathway.

Resistance to Metastatic Disease in STAT6-Deficient Mice Requires Hemopoietic and Nonhemopoietic Cells and Is IFN-γ Dependent

“…It has been hypothesized that the development of Th1 cells optimizes CD8-mediated tumor immunity (7), and hence STAT6 Ϫ/Ϫ mice were thought to be more tumor resistant because they predominantly make Th1 cells. In vivo depletion studies in the mammary carcinoma system, however, contradicted this hypothesis and demonstrated that although CD8 ϩ T cells are essential for tumor rejection by STAT6 Ϫ/Ϫ mice, CD4 ϩ T cells are not involved (3). In contrast, depletion of CD4 ϩ cells increases immunity in the fibrosarcoma system; however, additional studies suggest that the enhancement is due to depletion of regulatory CD4 ϩ NKT cells, rather than CD4 ϩ Th cells (1).…”

“…As an alternative explanation to Th1 vs Th2 CD4 ϩ helper cell ratio, it has been proposed that STAT6-deficient mice have enhanced immunity because they lack an inhibitor that blocks the development of tumor-reactive CD8 ϩ T cells (1,3). In the primary fibrosarcoma system, IL-13 produced by CD4 ϩ NKT cells has been hypothesized as the inhibitor (1).…”

“…They are resistant to recurrence of a primary fibrosarcoma (1), reject a transplanted mastocytoma (2), and have significantly reduced metastatic disease following challenge with a spontaneously metastatic mammary carcinoma (3). STAT6 Ϫ/Ϫ mice are deficient in responsiveness to IL-4 and IL-13, two cytokines essential for development of CD4 ϩ Th2 cells, and hence preferentially produce CD4 ϩ Th1 cells (4 -6).…”

“…BALB/c mice were inoculated with 7000 4T1 cells in the abdominal mammary gland on day 0 and given soluble IL-13R␣2-Fc (sIL-13R␣2-Fc) 3 …”

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

“…40). Previous studies implicated STAT6 as possible factor involved in immune suppression associated with myeloid cells (14,41,42). We have demonstrated important role of STAT3 in accumulation of Gr-1 ϩ IMC in cancer (13), and a number of groups demonstrated important role of STAT1 in regulation of iNOS activity (43,44).…”