TY - JOUR
T1 - Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression
AU - Griess, Brandon
AU - Mir, Shakeel
AU - Datta, Kaustubh
AU - Teoh-Fitzgerald, Melissa
N1 - Funding Information:
This work was financially supported by grants from the NIH R0I-CA182086A (Teoh-Fitzgerald), Redox Biology Pilot Project Fund (NTSBRDF, Uni. of Nebraska, Lincoln) (Teoh-Fitzgerald), and COBRE Nebraska Center for Cellular Signaling Collaborative Pilot Project grant (P30 GM106397). Brandon Griess was supported by the Eppley Institute in Cancer Biology Training Grant (NCI T32CA009476). EPR spectroscopy data were collected in the University of Nebraska EPR Spectroscopy Core, which is supported in part, by the National Institute of General Medical Sciences of the National Institute of Health (P30GM103335) awarded to the University of Nebraska's Redox Biology Center.
Funding Information:
This work was financially supported by grants from the NIH R0I-CA182086A (Teoh-Fitzgerald), Redox Biology Pilot Project Fund (NTSBRDF, Uni. of Nebraska, Lincoln) (Teoh-Fitzgerald), and COBRE Nebraska Center for Cellular Signaling Collaborative Pilot Project grant ( P30 GM106397 ). Brandon Griess was supported by the Eppley Institute in Cancer Biology Training Grant ( NCI T32CA009476 ). EPR spectroscopy data were collected in the University of Nebraska EPR Spectroscopy Core, which is supported in part, by the National Institute of General Medical Sciences of the National Institute of Health ( P30GM103335 ) awarded to the University of Nebraska's Redox Biology Center. Appendix A
Publisher Copyright:
© 2019
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Tumor associated macrophages (TAM) enhance the aggressiveness of breast cancer via promoting cancer cell growth, metastasis, and suppression of the patient's immune system. These TAMs are polarized in breast cancer with features more closely resembling the pro-tumorigenic and immunosuppressive M2 type rather than the anti-tumor and pro-inflammatory M1 type. The goal of our study was to examine primary human monocyte-derived M1 and M2 macrophages for key redox differences and determine sensitivities of these macrophages to the redox-active drug, MnTE-2-PyP5+. This compound reduced levels of M2 markers and inhibited their ability to promote cancer cell growth and suppress T cell activation. The surface levels of the T cell suppressing molecule, PD-L2, were reduced by MnTE-2-PyP5+ in a dose-dependent manner. This study also examined key differences in ROS generation and scavenging between M1 and M2 macrophages. Our results indicate that M2 macrophages have lower levels of reactive oxygen species (ROS) and lower production of extracellular hydrogen peroxide compared to the M1 macrophages. These differences are due in part to reduced expression levels of pro-oxidants, Nox2, Nox5, and the non-enzymatic members of the Nox complex, p22phox and p47phox, as well as higher levels of antioxidant enzymes, Cu/ZnSOD, Gpx1, and catalase. More importantly, we found that despite having lower ROS levels, M2 macrophages require ROS for proper polarization, as addition of hydrogen peroxide increased M2 markers. These TAM-like macrophages are also more sensitive to the ROS modulator and a pan-Nox inhibitor. Both MnTE-2-PyP5+ and DPI inhibited expression levels of M2 marker genes. We have further shown that this inhibition was partly mediated through a decrease in Stat3 activation during IL4-induced M2 polarization. Overall, this study reveals key redox differences between M1 and M2 primary human macrophages and that redox-active drugs can be used to inhibit the pro-tumor and immunosuppressive phenotype of TAM-like M2 macrophages. This study also provides rationale for combining MnTE-2-PyP5+ with immunotherapies.
AB - Tumor associated macrophages (TAM) enhance the aggressiveness of breast cancer via promoting cancer cell growth, metastasis, and suppression of the patient's immune system. These TAMs are polarized in breast cancer with features more closely resembling the pro-tumorigenic and immunosuppressive M2 type rather than the anti-tumor and pro-inflammatory M1 type. The goal of our study was to examine primary human monocyte-derived M1 and M2 macrophages for key redox differences and determine sensitivities of these macrophages to the redox-active drug, MnTE-2-PyP5+. This compound reduced levels of M2 markers and inhibited their ability to promote cancer cell growth and suppress T cell activation. The surface levels of the T cell suppressing molecule, PD-L2, were reduced by MnTE-2-PyP5+ in a dose-dependent manner. This study also examined key differences in ROS generation and scavenging between M1 and M2 macrophages. Our results indicate that M2 macrophages have lower levels of reactive oxygen species (ROS) and lower production of extracellular hydrogen peroxide compared to the M1 macrophages. These differences are due in part to reduced expression levels of pro-oxidants, Nox2, Nox5, and the non-enzymatic members of the Nox complex, p22phox and p47phox, as well as higher levels of antioxidant enzymes, Cu/ZnSOD, Gpx1, and catalase. More importantly, we found that despite having lower ROS levels, M2 macrophages require ROS for proper polarization, as addition of hydrogen peroxide increased M2 markers. These TAM-like macrophages are also more sensitive to the ROS modulator and a pan-Nox inhibitor. Both MnTE-2-PyP5+ and DPI inhibited expression levels of M2 marker genes. We have further shown that this inhibition was partly mediated through a decrease in Stat3 activation during IL4-induced M2 polarization. Overall, this study reveals key redox differences between M1 and M2 primary human macrophages and that redox-active drugs can be used to inhibit the pro-tumor and immunosuppressive phenotype of TAM-like M2 macrophages. This study also provides rationale for combining MnTE-2-PyP5+ with immunotherapies.
KW - Breast cancer
KW - Immunosuppression
KW - ROS
KW - SOD mimetics
KW - Stat3
KW - Tumor associated macrophages
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U2 - 10.1016/j.freeradbiomed.2019.12.018
DO - 10.1016/j.freeradbiomed.2019.12.018
M3 - Article
C2 - 31863907
AN - SCOPUS:85076705187
VL - 147
SP - 48
EP - 60
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
ER -