Reversing Breast Cancer-Induced Immune Suppression
Abstract
Previous studies have shown that MDSC block adaptive anti-tumor immunity by producing high levels of oxidizing agents such as reactive oxygen species (ROS), nitric oxide (NO), and peroxynitrite. Despite high levels of the toxic oxidizing agents, MDSC survive and suppress anti-tumor immunity. We hypothesize that MDSC survival is mediated by the antioxidant-regulating transcription factor Nrf2. To test this hypothesis, wild type and Nrf2-/- BALB/c and C57BL/6 mice were injected with 4T1 mammary carcinoma cells or MC38 colon carcinoma cells, respectively. Tumor-bearing mice were assayed weekly for percentage of MDSC in the blood and for MDSC levels of ROS and glutathione, MDSC production of H2O2 and suppressive activity, and MDSC apoptosis. Mice were also followed for survival. Nrf2-/- MDSC had more ROS and less glutathione than wild type MDSC, indicating that Nrf2-/- MDSC were more oxidatively stressed. Nrf2-/- MDSC were more apoptotic than wild type MDSC. Nrf2-/- and wild type mice had similar rates of primary tumor growth and MDSC accumulation, but tumor-bearing Nrf2-/- mice lived longer, indicating that Nrf2 contributes to tumor progression. Nrf2-/- MDSC produce less H2O2 and were less suppressive than wild type MDSC. These data are consistent with our hypothesis that Nrf2 regulates MDSC survival and suppressive activity, resulting in less suppressive MDSC in Nrf2-/- mice, thereby increasing anti-tumor immunity against metastatic disease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2014
- Accession Number
- ADA597797
Entities
People
- Daniel W. Beury
- Suzanne Ostrand-Rosenberg
Organizations
- University of Maryland, Baltimore