Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that inhibit anti-tumor immune responses. Recruitment out of the bone marrow and localization at the tumor site are important for effective suppression. We have previously demonstrated that mast cells are critical for the ability of MDSCs to promote tumor growth and metastasis. In this proposal we aim to further elucidate this interaction between MDSCs and mast cells through examination of two mast cell mediators, histamine and IL- 13. Histamine is a major mediator released by mast cells, and we have previously shown that MDSCs express histamine receptors 1 - 3, but not 4 and alter gene expression in response to histamine.
In Aim 1 we plan to demonstrate that histamine and activated mast cells alter the accumulation and suppressive capacity of MDSCs in vitro using T cell suppression assays and co-culture experiments. We will confirm the role of mast cell-derived histamine using in vivo tumor models in mice, whose mast cells do not produce histamine (mast cell-deficient mice reconstituted with histidine decarboxylase deficient bone marrow derived mast cells). IL-13 is another mediator secreted by mast cells, which has been reported to increase the suppressive enzymes in MDSCs. Our preliminary data suggests that IL-13 is acting as a chemotactic agent for MDSCs to the tumor site.
Aim 2 endeavors to understand the role of IL-13 in recruiting MDSCs. We will examine this using in vitro migration assays before moving into the in vivo models. Mast cell-deficient mice reconstituted with IL-13-/- mast cells will be challenged with tumor, and we will assess the trafficking of and signaling in MDSCs and tumor progression. We expect to see less tumor and fewer MDSCs in the tumor and liver of the mice with IL13-/- mast cells.
We propose to study the interaction between myeloid-derived suppressor cells (MDSCs) and mast cells in the context of cancer. This proposal aims to further elucidate the mediators of this interaction, specifically histamine and IL-13. Through better understanding of this communication, future treatments may modulate the effect of MDSCs, potentially enhancing the ability of the patient's immune system to reject the cancer.
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| Terracina, Krista P; Graham, Laura J; Payne, Kyle K et al. (2016) DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer. Cancer Immunol Immunother 65:1061-73 |
