Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression

The mouse 4T1 mammary carcinoma is a BALB/ c-derived tumor that spontaneously metastasizes and induces immune suppression. Although > 95% of wild type BALB/ c mice die from metastatic 4T1 tumor even if the primary mammary tumor is surgically removed, > 65% of BALB/ c mice with a deleted Signal Transducer Activator of Transcription 6 (STAT6) gene survive post-surgery. STAT6-deficiency also confers enhanced immunity against spontaneously developing breast cancer since NeuT(+/-) mice that are STAT6-deficient develop mammary tumors later and survive longer than NeuT(+/-) mice that are STAT6-competent. Rejection of metastastic disease and survival of STAT6-deficient mice after removal of primary tumor involve three mechanisms: ( 1) The generation of M1 type macrophages that produce nitric oxide and are tumoricidal; ( 2) A decrease to normal in the elevated levels of myeloid suppressor cells that accumulate during primary tumor growth; and ( 3) CD8(+) tumor-specific T lymphocytes. STAT6-deficient, but not wild type BALB/ c, mice generate nitric oxide producing macrophages because they lack the STAT6 transcription factor which is necessary for signaling through the type 2 IL-4R alpha complex, and which induces the production of arginase instead of nitric oxide.