Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and nonhemopoietic cells and is IFN-gamma dependent.
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-gamma(-/-) mice indicate that IFN-gamma is essential for immunity. Therefore, immunosurveillance in STAT6(-/-) mice facilitates survival against metastatic cancer via an IFN-gamma-dependent mechanism involving hemopoietic and nonhemopoietic derived cells, and is not exclusively dependent on counteracting IL-13 or CD4(+)CD25(+) T cells.
Ostrand-Rosenberg
Suzanne
S
Department of Biological Sciences, University of Maryland, 1000 Hilltop Circle, Baltimore, MD 21250, USA. srosenbe@umbc.edu
Clements
Virginia K
VK
Terabe
Masaki
M
Park
Jong Myun
JM
Berzofsky
Jay A
JA
Dissanayake
Samudra K
SK
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000601:surgery; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000601:surgery; D006410:Hematopoiesis / Q000235:genetics* / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000601:surgery; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000601:surgery; D008212:Lymphocyte Depletion; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000276:immunology*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000637:transplantation
D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma