Immune Suppression and Inflammation in the Progression of Breast Cancer

Abstract

Abstract : Epidemiological and experimental evidence supports the concept that chronic inflammation promotes the development and progression of cancers; however, the mechanisms underlying this relationship are poorly understood. We have demonstrated previously that secretion of the pro-inflammatory cytokine interleukin 1beta (IL-1beta) from 4T1 mammary carcinoma cells (4T1/IL-1beta) promotes tumor progression and decreases the survival of tumor-bearing animals. Tumor progression in many patients and experimental animals with cancer is frequently associated with the expansion of a population of myeloid cells, termed Myeloid-derived Suppressor Cells (MDSC). These cells have potent immunosuppressive activity and inhibit both innate and adaptive immunity by inhibiting T cell activation, NK cell cytotoxicity, and reducing the number of mature dendritic cells. Chronic inflammation at the tumor site enhances and alters the quality of MDSC by inducing a phenotypically and functionally distinct population of MDSC, which are more potent suppressors of CD8+ T cells. Using mice deficient for the IL-1 receptor (IL-1R-/-), we demonstrate that reducing inflammation delays tumor growth, the development of lung metastases, and the expansion of MDSC. MDSC in an inflammation-deficient environment are phenotypically and functionally similar to MDSC in wild-type BALB/c mice. Here we demonstrate that inflammation-induced MDSC skew immunity towards a type-2 response by reducing IL-12 production by macrophages and producing elevated levels of IL-10. In addition to the delays in MDSC induction, reducing inflammation prevent the accumulation of a more potent population of MDSC induced by inflammation, as MDSC from IL-1R-/- mice produce similar levels of IL-10 as BALB/c mice. These data suggest that limiting tumor-associated inflammation may delay the onset of systemic immune suppression that accompanies breast cancer progression and may enhance the efficacy of current and future therapies.