Reversing Breast Cancer-Induced Immune Suppression
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Date
2015-01-01
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Department
Biological Sciences
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Biological Sciences
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This item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.edu
Distribution Rights granted to UMBC by the author.
Distribution Rights granted to UMBC by the author.
Abstract
The immune system is capable of eradicating transformed cells. However, tumor cells and host cells present in the tumor secrete pro-inflammatory mediators that promote the accumulation and activity of myeloid-derived suppressor cells (MDSC), which potently suppress anti-tumor immunity. MDSC and macrophages are present in most solid tumors and it is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity; however, interactions between tumor cells and MDSC or macrophages are less well studied. Using four murine tumor cell lines, we examined potential interactions between these cells in vitro and in vivo. In vitro studies demonstrated that MDSC-secreted IL-10 decreased macrophage-derived IL-6 and TNFα, and increased nitric oxide (NO). IL-6 indirectly decreased MDSC IL-10. Tumor cells increased MDSC IL-6 and vice versa; and increased macrophage IL-6 and NO, and decreased macrophage TNFα. Tumor-cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. In vivo studies identified that IL-6 and IL-10 were produced by stromal cells in the tumor. These results demonstrate that MDSC, macrophage, and tumor cell interactions potentially alter the inflammatory milieu within the tumor microenvironment and drive tumor growth. Release of reactive oxygen species (ROS) is one of the mechanisms used by MDSC to suppress anti-tumor immunity. Although ROS are toxic to most cells, MDSC survive despite their elevated content and release of ROS. Nuclear factor erythroid derived 2-like 2 (Nrf2) is a transcription factor that regulates a battery of genes which attenuate oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be due to their up-regulation of Nrf2. Murine studies demonstrated that Nrf2 enhanced MDSC suppressive activity and increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis. Nrf2 did not affect circulating levels of MDSC in tumor-bearing mice since the decreased apoptotic rate of tumor-infiltrating MDSC was balanced by a decreased rate of differentiation from bone marrow progenitor cells. These results demonstrate that Nrf2 regulates the generation, survival and suppressive potency of MDSC, and that a feedback homeostatic mechanism maintains a steady-state level of circulating MDSC in tumor-bearing individuals.