Modulating Cytokines to Polarize Tumor-Infiltrating Immune Cells in the Tumor Microenvironment by Special Extracts of Eriobotrya japonica

Cytokines play key role in immune responses to developing tumors and hence regarded as important targets for immunomodulation. Manipulation of cytokine actions provides innovative strategies for enhancing the activity of dendritic cells, macrophages and polarizing towards T helper 1 type response within tumor microenvironment. One of these approaches could be the employment of immunomodulators to participate in achieving this polarized cellular response via their immunopotentiating capabilities. Eriobotrya japonica (EJ) folium has been known to possess both immunopotentiating and antitumor activities in vitro. Given the above, the present study sought the in vivo immunomodulatory effect on interferon-gamma (IFN-γ), interleukin-17 (IL-17), and transforming growth factor-beta 1 (TGF-β1) evoked by water-extracts prepared from EJ leaves in the intra-organ environment of normal mice spleen, lung and blood tissues and further explored these immunomodulatory potentials in the microenvironment of Meth-A-fibrosarcoma bearing mice and immune active sites. Determination of the three cytokines kinetics over 0, 2, 6, 24, and 48 hours in spleen, lungs, and blood of normal mice induced by EJ hydrophilic leaf extract (EJHE) and EJHE-water residue (WR), prepared from butanol extraction, at 10 µg/ml showed that EJHE and EJHE-WR increased IFN-γ production from the spleen and lung tissues iv over 6-48 hours and in blood over 6-48 hours upon EJHE-WR administration. Furthermore, in contrast to the discerned increase of IFN-γ in the spleen, TGF-β1 was down-regulated in response to EJHE and EJHE-WR administration for as long as 48 hours. The latter induced responses, however, were not seen in Meth-A fibrosarcoma-bearing mice. In the latter model, triple i.p. injections of EJHE at 10 µg/ml 24 hours apart, increased significantly spleen IFN-γ production whereas EJHE-WR increased significantly IFN-γ, TGF-β1 and IL-17 production within the tumor microenvironment of Meth-A fibrosarcoma. In addition, the present results revealed prolonged survival of mice inoculated i.p. with Meth-A cells following three times/week of EJHE-WR i.p. administration. The latter prolonged survival effect was not seen with EJHE. These results conclude that 10 μg/ml EJHE and EJHE-WR increase the production of IFN-γ and suppress the production of TGF-β1 levels in normal mice spleen. In the tumor microenvironment of Meth-A fibrosarcoma, however, triple injections of EJHE and EJHE-WR at least are needed to modulate cytokines level. Thus, the therapeutic value of EJHE and EJHE-WR as anticancer agent merits further investigation to promote a more rationale utilization. This could be performed by understanding of the effect of immunomodulators' constituents on the cellular components of …