CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model. Issue 1 (September 2014)

• Record Type: Journal Article
• Authors: Oghumu, Steve; Varikuti, Sanjay; Terrazas, Cesar; Kotov, Dmitri; Nasser, Mohd W.; Powell, Catherine A.; Ganju, Ramesh K.; Satoskar, Abhay R.
• Is Part Of: Immunology. Volume 143:Issue 1(2014:Sep.)
• Page Start: 109
• Page End: 119
• Publication Date: 2014-09
• Subjects: Immunology -- Periodicals
• DOI: 10.1111/imm.12293
• Languages: English
• ISSNs: 0019-2805

Abstract

<abstract abstract-type="main" id="imm12293-abs-0001"> <title>Summary</title> <p>Tumor associated macrophages play a vital role in determining the outcome of breast cancer. We investigated the contribution of the chemokine receptor CXCR3 to antitumor immune responses using a <italic>cxcr3</italic> deficient mouse orthotopically injected with a PyMT breast cancer cell line. We observed that <italic>cxcr3</italic> deficient mice displayed increased IL‐4 production and M2 polarization in the tumors and spleens compared to WT mice injected with PyMT cells. This was accompanied by larger tumor development in <italic>cxcr3</italic><sup><italic>−/−</italic></sup> than in WT mice. Further, tumor‐promoting myeloid derived immune cell populations accumulated in higher proportions in the spleens of <italic>cxcr3</italic> deficient mice. Interestingly, <italic>cxcr3</italic><sup><italic>−/−</italic></sup> macrophages displayed a deficiency in up‐regulating inducible nitric oxide synthase after stimulation by either IFN‐<italic>γ</italic> or PyMT supernatants. Stimulation of bone marrow derived macrophages by PyMT supernatants also resulted in greater induction of arginase‐1 in <italic>cxcr3</italic><sup><italic>−/−</italic></sup> than WT mice. Further, <italic>cxcr3</italic><sup>−/−</sup> T cells activated with CD3/CD28 <italic>in vitro</italic> produced greater amounts of IL‐4 and IL‐10 than T cells from WT mice. Our data suggests that a greater predisposition of <italic>cxcr3</italic> deficient macrophages towards M2 polarization contributes to an enhanced tumor promoting environment in <italic>cxcr3</italic> deficient mice. Although CXCR3 is known to be expressed on some macrophages, this is the first report that demonstrates a role for CXCR3 in macrophage polarization and subsequent breast tumor outcomes. Targeting CXCR3 could be a potential therapeutic approach in the management of breast cancer tumors.</p> </abstract>