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

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Abstract

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-4Rα complex, and which induces the production of arginase instead of nitric oxide.

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Acknowledgements

We thank Ms. Cordula Davis for her help in monitoring tumor progression in the neuT+/− and STAT6−/− neuT+/− mice and Dr. Beth Pulaski for performing the carrageenan experiment. We appreciate the excellent care given to our mouse colony by Ms. Sandra Mason. These studies were supported by NIH grants R01 CA52527 and R01 CA84232, and by U.S. Army Breast Cancer Program Grant DAMD-17-01-1-0312.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD, 21250, USA

    Pratima Sinha, Virginia K. Clements, Seth Miller & Suzanne Ostrand-Rosenberg

Authors
  1. Pratima Sinha
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  2. Virginia K. Clements
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  3. Seth Miller
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  4. Suzanne Ostrand-Rosenberg
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Corresponding author

Correspondence to Suzanne Ostrand-Rosenberg.

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This article is a symposium paper from the conference “Tumor Escape and Its Determinants”, held in Salzburg, Austria, on 10–13 October 2004

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Sinha, P., Clements, V.K., Miller, S. et al. Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother 54, 1137–1142 (2005). https://doi.org/10.1007/s00262-005-0703-4

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  • DOI: https://doi.org/10.1007/s00262-005-0703-4

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