CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model

Abstract

SummaryTumor 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 cxcr3 deficient mouse orthotopically injected with a PyMT breast cancer cell line. We observed that cxcr3 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 cxcr3 À/À than in WT mice. Further, tumor-promoting myeloid derived immune cell populations accumulated in higher proportions in the spleens of cxcr3 deficient mice. Interestingly, cxcr3 À/À macrophages displayed a deficiency in up-regulating inducible nitric oxide synthase after stimulation by either IFN-c or PyMT supernatants. Stimulation of bone marrow derived macrophages by PyMT supernatants also resulted in greater induction of arginase-1 in cxcr3 À/À than WT mice. Further, cxcr3 À/À T cells activated with CD3/CD28 in vitro produced greater amounts of IL-4 and IL-10 than T cells from WT mice. Our data suggests that a greater predisposition of cxcr3 deficient macrophages towards M2 polarization contributes to an enhanced tumor promoting environment in cxcr3 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.

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

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Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells

“…Thus, the phenotype of these cells was most consistent with the reported phenotype of TNFa and iNOS-producing DCs (TIP-DC; refs. [36][37][38]. Although these cells are called "TIP-DCs," it has been suggested that these cells can be considered inflammatory macrophages (38).…”

The Role of CXCR3/Ligand Axis in Cancer

“…A recent study showed that CXCR3 expression was important for macrophage polarization in a murine breast cancer model. The study demonstrated that the absence of host CXCR3 expression led to increased tumor growth and progression with enhanced levels of TAMs with M2 polarization [26]. The absence of macrophage CXCR3 expression led to M2 polarization and regulated innate and immune cell-mediated anti-tumor responses that present important therapeutic implications for breast cancer.…”