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Title: Scutellaria flavonoids inhibit tumor-mediated induction of Treg cells via inhibition of TGF-ß1 activity

Author
item DANDAWATE, SAGAR - Wayne State University
item WILLIAMS, LINFORD - Wayne State University
item JOSHEE, NIRMAL - Fort Valley State University
item Rimando, Agnes
item MITTAL, SANDEEP - Wayne State University
item THAKUR, ARCHANA - Wayne State University
item LUM, LAURENCE - Wayne State University
item PARAJULI, PRAHLAD - Wayne State University

Submitted to: Cancer Immunology and Immunotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/14/2011
Publication Date: 11/6/2011
Citation: Dandawate, S., Williams, L., Joshee, N., Rimando, A.M., Mittal, S., Thakur, A., Lum, L., Parajuli, P. 2011. Scutellaria flavonoids inhibit tumor-mediated induction of Treg cells via inhibition of TGF-ß1 activity. Cancer Immunology and Immunotherapy. 61:701-711.

Interpretive Summary: One of the strategies employed to treat cancer including gliomas (tumor that starts in the brain or spine) is immunotheraphy, the use immune system to counter malignant tumor cells. One way to stimulate the patient’s immune system is by administering cancer vaccines. However, sub-optimal response to therapeutic cancer vaccines has become evident. This is due to increased activity of regulatory T-cells (Treg, cells that suppress activation of the immune system), which is induced by the cancer cells including gliomas. High-grade gliomas are known to suppress the immune responses via secretion of transforming growth factor-beta 1 (TGF-ß1), a protein that plays a role in controlling proliferation of T cells. TGF-ß1 is critical in the expansion of pre-existing regulatory T cells. Scutellaria extracts or constituent flavonoids have shown encouraging anti-cancer activity in both pre-clinical and clinical studies against various tumors, including gliomas. We report here, for the first time, that Scutellaria flavonoids inhibit the secretion of TGF-ß1 as well as TGF-ß-induced Treg activity in malignant gliomas. Scutellaria ocmulgee leaf extract was administered to rats, which has been transplanted with gliomas in the subcutaneous tissue. We observed significant inhibition of TGF-ß1 and T reg cell frequency in the tumor as well as decrease in peripheral TGF-ß1 levels. Our studies showed Scutellaria extract could inhibit the T-cells’ response to TGF-ß1 via modulation of different signaling pathways. Overall, the present study suggests that Scutellaria extract may provide an opportunity for developing a novel adjuvant therapeutic strategy for malignant gliomas, which could potentially improve the disease outcome.

Technical Abstract: It has become evident that tumor-induced Treg cell activity is mostly responsible for the sub-optimal response to therapeutic vaccines. Development of neo-adjuvant strategies targeting TGF-ß and Treg cell activity is therefore imperative. Scutellaria extracts or constituent flavonoids have shown encouraging anti-cancer activity in both pre-clinical and clinical studies against various tumors, including gliomas. We report here, for the first time, that Scutellaria flavonoids inhibit the secretion of TGF-ß1 as well as TGF-ß-induced Treg activity in malignant gliomas. F344 rats, subcutaneously transplanted with F98 gliomas, were administered with Scutellaria ocmulgee leaf (SocL) extract. We observed significant inhibition of intra-tumoral TGF-ß1 and Treg cell frequency as well as peripheral TGF-ß1 levels, as determined by immunohistochemistry and ELISA, respectively, in SocL treated animals compared to the control groups. Frequency of intra-tumoral CD3+ T cells were however unaffected, indicating that Scutellaria preferentially inhibited the induction of Treg cells in gliomas, probably via inhibition of TGF-ß1 activity. SocL extract and wogonin also inhibited glioma-induced, TGF-ß-mediated Treg activity in vitro in a Treg induction/expansion model. The functional activity of Treg cells and their inhibition by Scutellaria flavonoids were confirmed using a co-culture suppression assay. Scutellaria flavonoids also inhibited the secretion of IL-10 in Treg culture; whereas the level of IL-2 was either unchanged or marginally enhanced. We also observed an inhibition of Smad-3, GSK-3ß and ERK1/2 signaling by SocL and wogonin in Treg cells, while phosphorylation of P38 MAPK was considerably enhanced, indicating that Scutellaria flavonoids could inhibit the T cells’ response to TGF- ß1 via modulation of both Smad and non-Smad signaling pathways. Overall, the present study suggests that Scutellaria flavonoids can potentially reverse tumor-mediated immune suppression via inhibition of TGF- ß1 secretion as well as via inhibition of T cells’ response to TGF- ß1. This may provide an opportunity for developing a novel adjuvant therapeutic strategy for malignant gliomas, combining Scutellaria flavonoids with immunotherapy and chemo/radio therapeutic regimen, which could potentially improve the disease outcome.