Abstract 5180: Allergic pulmonary inflammation accelerates breast cancer metastasis via increase of MDSCs in the lung microenvironment

Abstract

Abstract Disseminated metastasis accounts for majority of cancer-related deaths. Lungs are one of the common sites for breast cancer metastasis. Inflammation is known to contribute to tumor initiation and metastasis. Since it is not known the effect of pre-existing inflammation on metastasis, we combined a well-established model of allergic pulmonary inflammation with breast cancer model. Using this model, we found that allergen sensitized mice implanted with 4T1 mammary tumors had a five-fold increase in metastatic foci formation compared to the 4T1 controls. Further, tumor cell infiltration in the lungs was three-times faster in allergic 4T1 tumor bearing mice. More importantly, allergic 4T1 tumor bearers showed accelerated primary tumor growth and shorter survival rate. It is known that one of the contributing factors in metastasis is an increase in myeloid derived suppressor cells (MDSC). Myeloid derived subpopulations are also known to be present in the lungs of mice and humans with allergic pulmonary inflammation. Since MDSCs play a key role in the immunosuppressive process associated with both inflammation and metastasis, we hypothesized that allergic pulmonary inflammatory microenvironment attracts myeloid subpopulations that support incoming mammary tumors cells and accelerate metastasis. To test this hypothesis, we assessed the alterations in MDSC subpopulations in the lungs of mice with pre-existing pulmonary inflammation (ragweed mice). We found an increase in the monocytic (CD11b+Ly6ChighLy6G-), granulocytic (CD11b+Ly6ClowLy6G+) and macrophages (CD11b+F4/80+CD11c+) subpopulations in mice with allergic pulmonary inflammation prior to tumor inoculation. These populations were further increased after 4T1 tumor cell inoculation (ragweed 4T1 mice). To determine the role of MDSCs in contributing to accelerated metastasis, we assessed the pro-inflammatory mediators secreted by these cells known to play a role in tumor growth and metastasis. Chemokines such as CCL2/MCP-1, CXCL2/IL-8 and their receptors, CCR2 and CXCR2 were increased in ragweed mice and these levels were further enhanced in ragweed 4T1 tumor bearers. Depletion of MDSCs prior to tumor cell inoculation in ragweed mice decreased pulmonary inflammatory mediators resulting in decreased tumor growth and metastasis in ragweed 4T1 tumor bearing mice. Targeting specific immune populations could lead to a safer and more efficient strategies against breast cancer metastasis. Note: This abstract was not presented at the meeting. Citation Format: Stephania Libreros, Ramon Garcia-Areas, Nathalia Gazaniga, Philip Robinson, Vijaya Iragavarapu-Charyulu. Allergic pulmonary inflammation accelerates breast cancer metastasis via increase of MDSCs in the lung microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5180. doi:10.1158/1538-7445.AM2015-5180