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Myeloid-derived suppressor cell function is reduced by Withaferin A, a potent and abundant component of Withania somnifera root extract


Myeloid cells play a crucial role in tumor progression. The most common tumor-infiltrating myeloid cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs). These cells promote tumor growth by their inherent immune suppressive activity which is enhanced by their cross-talk. The root extract of the plant Withania somnifera (Ashwagandha) (WRE) has been reported to reduce tumor growth. HPLC analysis identified Withaferin A (WA) as the most abundant constituent of WRE and led us to determine whether the anti-tumor effects of WRE and WA involve modulating MDSC and TAM activity. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, thus polarizing immunity to a pro-tumor type 2 phenotype. In vitro treatment with WA decreased MDSC production of IL-10 and prevented additional MDSC production of IL-10 generated by MDSC–macrophage cross-talk. Macrophage secretion of IL-6 and TNFα, cytokines that increase MDSC accumulation and function, was also reduced by in vitro treatment with WA. Much of the T-cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduced MDSC production of ROS through a STAT3-dependent mechanism. In vivo treatment of tumor-bearing mice with WA decreased tumor weight, reduced the quantity of granulocytic MDSC, and reduced the ability of MDSC to suppress antigen-driven activation of CD4+ and CD8+ T cells. Thus, adjunctive treatment with WA reduced myeloid cell-mediated immune suppression, polarized immunity toward a tumor-rejecting type 1 phenotype, and may facilitate the development of anti-tumor immunity.

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We thank Drs. James B. McMahon, Kirk R. Gustafson, and Thomas J. Sayers (NIH) for helpful discussions, and Dr. Adam I. Marcus (Emory) for sharing his protocol for the preparation of the WRE extract. This study was supported by NIH RO1CA84232, NIH RO1CA115880, NIHRO1GM021248, and American Cancer Society IRG-97-153-07.

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The authors declare no financial or commercial conflict of interest.

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Correspondence to Pratima Sinha.

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Sinha, P., Ostrand-Rosenberg, S. Myeloid-derived suppressor cell function is reduced by Withaferin A, a potent and abundant component of Withania somnifera root extract. Cancer Immunol Immunother 62, 1663–1673 (2013). https://doi.org/10.1007/s00262-013-1470-2

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  • Tumor immunology
  • Tumor-induced immune suppression
  • T-cell activation
  • Immunotherapy
  • Withaferin A
  • Withania somnifera