Reversing Breast Cancer-Induced Immune Suppression
Abstract
Tumor-induced myeloid-derived suppressor cells (MDSC) contribute to immune suppression in tumor-bearing individuals and are a major obstacle to effective immunotherapy. Reactive oxygen species (ROS) are one of the mechanisms used by MDSC to suppress T cell activation. Although ROS are toxic to most cells, MDSC are not negatively impacted by their production of ROS. Nuclear factor erythroid derived 2-like 2 (Nrf2) is a transcription factor that regulates a battery of genes which attenuate oxidative stress and therefore we hypothesized that MDSC resistance to ROS may be due to their up-regulation of Nrf2. To test this hypothesis, we utilized BALB/c and C57BL/6 mice bearing 4T1 mammary carcinoma and MC38 colon carcinoma, respectively. MDSC from the peripheral blood of Nrf2-/-mice with 4T1-tumors were more oxidatively stressed and apoptotic, produced less H2O2, and were less suppressive than MDSC from Nrf2+/+ mice, indicating that Nrf2 sustainsMDSC survival and suppressive activity. Primary tumors and levels of MDSC were similar in Nrf2-/- and Nrf2+/+ mice, but Nrf2-/- mice survived longer. Since Nrf2-/- MDSC were more apoptotic, but Nrf2-/- and Nrf2+/+ tumor-bearing mice had similar levels of MDSC, we hypothesized that MDSC differentiate more rapidly from Nrf2-/- than from Nrf2+/+ progenitor cells. This hypothesis was confirmed because Nrf2-/- bone marrow cells cultured with IL-6 and GM-CSF, produced more MDSC than similar cultures of Nrf2+/+ progenitor cells. These data demonstrate that Nrf2 facilitates tumor progression by increasing MDSC-mediated suppression and by delaying MDSC turnover, and identify Nrf2 as a potential therapeutic target for reducing tumor-induced immune suppression and enhancing cancer immunotherapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2014
- Accession Number
- ADA619247
Entities
People
- Daniel W. Beury
- Suzanne Ostrand-Rosenberg
Organizations
- University of Maryland, Baltimore