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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance
Pratima Sinha1, Virginia K Clements, Suzanne Ostrand-Rosenberg
1Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, 21250, USA.
Abstract:
CD1-deficient mice reject established, disseminated 4T1 metastatic mammary cancer and survive indefinitely if their primary mammary tumors are surgically removed. This highly effective immune surveillance is due to three interacting mechanisms: (a) the generation of inducible nitric oxide synthase (iNOS)-producing M1 macrophages that are tumoricidal for 4T1 tumor cells; (b) a rapid decrease in myeloid-derived Gr1(+)CD11b(+) suppressor cells that are elevated and down-regulate the CD3zeta chain when primary tumor is present and that suppress T cells by producing arginase; and (c) production of activated lymphocytes. Macrophages from wild-type BALB/c mice are polarized by interleukin-13 (IL-13) towards a tumor-promoting M2 phenotype, thereby inhibiting the generation of tumoricidal M1 macrophages. In contrast, CD1(-/-) mice, which are deficient for IL-13 because they lack IL-13-producting NKT cells, generate M1 macrophages that are cytotoxic for 4T1 via the production of nitric oxide. Although tumoricidal macrophages are a necessary component of immune surveillance in CD1(-/-) mice, they alone are not sufficient for tumor resistance because IL-4Ralpha(-/-) mice have M1 macrophages and retain high levels of myeloid suppressor cells after surgery; in addition, they are susceptible to 4T1 metastatic disease. These results show that effective immune surveillance against established metastatic disease is negatively regulated by IL-13 and requires the induction of tumoricidal M1 macrophages and lymphocytes combined with a reduction in tumor-induced myeloid suppressor cells.
Insights
CD1-deficient mice reject metastatic mammary cancer through enhanced immune surveillance. This involves tumor-killing M1 macrophages and activated lymphocytes, alongside reduced suppressor cells, highlighting IL-13
Area of Science:
- Immunology
- Cancer Biology
- Infectious Disease
Background:
- Established, disseminated 4T1 metastatic mammary cancer is rejected by CD1-deficient mice post-primary tumor removal.
- Immune surveillance in wild-type mice is hampered by interleukin-13 (IL-13) polarizing macrophages to a tumor-promoting M2 phenotype.
- IL-13 also contributes to elevated myeloid-derived suppressor cells that inhibit T cell responses.
Purpose of the Study:
- To elucidate the mechanisms of immune surveillance against metastatic mammary cancer in CD1-deficient mice.
- To investigate the role of IL-13 and macrophage polarization in regulating anti-tumor immunity.
- To identify key cellular components required for resistance to established metastatic disease.
Main Methods:
- Comparison of immune responses in CD1-deficient, wild-type BALB/c, and IL-4Ralpha-deficient mice.
- Analysis of macrophage polarization (M1 vs. M2 phenotype) and function.
- Assessment of myeloid-derived suppressor cell levels and their impact on T cell responses.
- Evaluation of nitric oxide production by macrophages and lymphocyte activation.
Main Results:
- CD1-deficient mice exhibit enhanced immune surveillance, rejecting 4T1 tumors due to iNOS-producing M1 macrophages and reduced suppressor cells.
- Absence of IL-13 in CD1-deficient mice prevents M2 polarization, promoting cytotoxic M1 macrophage generation.
- Tumoricidal macrophages and lymphocytes, coupled with reduced suppressor cells, are essential for resistance, as demonstrated by IL-4Ralpha(-/-) mice susceptibility.
Conclusions:
- Effective immune surveillance against established metastatic mammary cancer is negatively regulated by IL-13.
- Resistance requires the synergistic action of tumoricidal M1 macrophages, activated lymphocytes, and diminished myeloid-derived suppressor cells.
- Targeting IL-13 and modulating macrophage polarization presents a potential therapeutic strategy for metastatic breast cancer.
