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-4Ralpha complex, and which induces the production of arginase instead of nitric oxide.
Sinha
Pratima
P
Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Clements
Virginia K
VK
Miller
Seth
S
Ostrand-Rosenberg
Suzanne
S
D000818:Animals; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000502:physiology; D018793:Interleukin-13 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015534:Trans-Activators / Q000502:physiology
D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D009569:Nitric Oxide; D007371:Interferon-gamma