Withaferin A, a potent and abundant component of Withania somnifera root extract, reduces myeloid-derived suppressor cell function (P2103)

Myeloid cells play a crucial role in growth and metastasis of malignant tumors. Tumor infiltrating myeloid cells include myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. These cells infiltrate into tumor and suppress tumor immunity by their inherent immune suppressive activity which is enhanced by interactions with each other (cross-talk). The root extract of the plant Withania somnifera (WRE) has been reported to reduce tumor cell proliferation and angiogenesis. We hypothesize that WRE or its constituents impact tumor infiltrating myeloid cells and thereby boost anti-tumor immunity. HPLC and MS analysis revealed that Withaferin A (WA) is the most abundant constituent of WRE. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, promoting type-2 immunity. WA reduces constitutive and cross-talk induced IL-10 secretion from MDSC. Macrophage secretion of IL-6 and TNFa cytokines that are characteristic of M1-type macrophages and that also increase MDSC accumulation and function, are also reduced by WA. Much of the T cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduces MDSC production of ROS. Thus adjunctive treatment with WA has the potential to concomitantly reduce myeloid cell mediated immune suppression, to polarize immunity towards a tumor-rejecting type I phenotype, and to facilitate the development of anti-tumor immunity.