In the course of evaluating the antitumor effects in mice of a cytostatic traditional Chinese Medicine, Sheng Qi Formula (studies supported by the OCCAM program of the NCI), consisting of a water extract of 2 plant roots (Radx Astragali and Panax Notoginsenga (SQF), it was noted that its antitumor effect on 4T1 breast cancer was associated with marked and consistent suppression of peripheral MDSC. SQF inhibited IL-4R, Ly6G+/Gr1+, and CD11b+ cells, as well as IL-10, IL-1arginase and H2O2 production. In combination with gemcitabine, SQF markedly reduced the growth of 4T1 breast tumor in mice. Thus, reduction in the immunosuppressive populations of MDSC promoted the antitumor effect of gemcitabine. Studies of the mechanism suggest that tumor derived G-CSF and IL-1 divert the maturation of immature DC and other immune cells toward MDSC-like functions. As MDSC infiltrate tumors, they mature into tumor-promoting alternatively activated immunosuppressive macrophages (TAM's). Means of counteracting MDSC's and TAM's are in our future plans. It has recently become clear that a subset of T cells e.g. CD4+CD25+FoxP3+T regulatory (Treg) cells are essential in the maintenance of immune homeostasis and have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also protect tumors from immune rejection. Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is highly expressed by Tregs, unexpectantly results in their proliferative expansion and functional activation both in mice and in man. Most tumor infiltrating T cells (TIL's) actually express TNFR2 and are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.
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