-
[show abstract]
[hide abstract]
ABSTRACT: Trichosanthin (TCS), extracted from the Chinese medicinal herb Trichosanthes kirilowi, has shown promise for the inhibition of tumor growth. However, its immunomodulatory effect on tumor-host interaction remains unknown. In this study, we focused on the effect of TCS on murine anti-tumor immune response in the 3LL Lewis lung carcinoma tumor model and explored the possible molecular pathways involved. In addition to inhibiting cell proliferation and inducing apoptosis in the 3LL tumor, TCS retarded tumor growth and prolonged mouse survival more significantly in C57BL/6 immunocompetent mice than in nude mice. This reflected the fact that the host immune system was involved in tumor eradication. Using FACS analysis, we found that TCS increased the percentage of effector T cells, particularly Interferon-gamma (IFN-γ) producing CD4(+) and CD8(+) T cells from tumor-bearing mice. TCS also promoted the vigorous proliferation of antigen-specific effector T cells, markedly increased Th1 cytokine secretion and elicited more memory T cells in tumor-bearing mice, consequently enhancing the anti-tumor response and inducing immune protection. Furthermore, we found that TCS upregulated the expression of tumor suppressor in lung cancer 1 (TSLC1) in 3LL tumor cells and the expression of its ligand, class I-restricted T cell-associated molecule (CRTAM), in effector T cells. Blocking TSLC1 expression with small interfering RNA (siRNA) significantly eliminated the effects of TCS on the proliferation and cytokine secretion of effector T cells, suggesting that TCS enhances anti-tumor immune response at least partially by boosting the interaction between TSLC1 and CRTAM. Collectively, our data demonstrate that TCS not only affects tumor cells directly, but also enhances anti-tumor immunity via the interaction between TSLC1 and CRTAM. These findings may lead to the development of a novel approach for tumor regression.
Cellular & molecular immunology 05/2011; 8(4):359-67. · 2.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Using TLR agonists in cancer treatment can have either beneficial or detrimental effects. Therefore, it is important to determine their effect on the tumor growth and understand the underlying mechanisms in animal tumor models. In this study, we report a general immunotherapeutic activity of a synthetic bacterial lipoprotein (BLP), a TLR1/TLR2 agonist, on established lung carcinoma, leukemia, and melanoma in mice. Systemic treatment of 3LL tumor-bearing mice with BLP, but not LPS, led to a dose-dependent tumor regression and a long-lasting protective response against tumor rechallenge. The BLP-mediated tumor remission was neither mediated by a direct tumoricidal activity nor by innate immune cells, because it lacked therapeutic effect in immunodeficient SCID mice. Instead, BLP treatment reduced the suppressive function of Foxp3(+) regulatory T cells (Tregs) and enhanced the cytotoxicity of tumor-specific CTL in vitro and in vivo. Furthermore, adoptive cotransfer of BLP-pretreated but not untreated CTL and Tregs from wild-type but not from TLR2(-/-) mice was sufficient to restore antitumor immunity in SCID mice by reciprocally modulating Treg and CTL function. These results demonstrate that the TLR1/TLR2 agonist BLP may have a general tumor therapeutic property involving reciprocal downregulation of Treg and upregulation of CTL function. This property may play an important role in the development of novel antitumor strategies.
The Journal of Immunology 02/2011; 186(4):1963-9. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Characterized as a mitotic inhibitor, paclitaxel has gained importance as a promising agent for the treatment of advanced non-small cell lung cancer (NSCLC). However, whether paclitaxel has immune modulatory effects remains unclear. In this study, we analyzed 55 peripheral blood samples from NSCLC patients who underwent paclitaxel-based chemotherapy. We found that among the lymphocyte subsets, paclitaxel selectively decreased the size of the regulatory T cell (Treg) population rather than other subsets including effector T cells (Teff). Apoptosis by upregulating the expression of the cell death receptor Fas (CD95) contributed to the reduced cell number of Treg. Importantly, the inhibitory function of Treg was significantly impaired, while the production of Th1 cytokines IFN-gamma and IL-2 and the expression of the activation marker CD44 among CD4(+) and CD8(+) T cells were augmented after paclitaxel treatment. These results strongly demonstrated that paclitaxel-based chemotherapy played important roles in modulating immune responses.
Clinical Immunology 10/2008; 129(2):219-29. · 4.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a powerful immune-stimulating factor that helps to generate a systemic, strong, and long-lasting immune response. However, whether the transduction of GM-CSF to tumor cell results in tumor regression and optimizes local immune microenvironment remains to be investigated. In this study, using an experimental murine tumor model, we demonstrated that the in vivo growth of 3LL tumor cells modified with the GM-CSF gene (3LL-GM) was inhibited even when the tumor diameter was over 7 mm (big tumor), and mice inoculated with GM-CSF gene-modified 3LL cells survived over 90 days, whereas mice inoculated with control parental 3LL cells and 3LL cells transduced with control vector all succumbed to the tumor by day 17 after tumor inoculation. Further analysis showed that targeted expression of GM-CSF in 3LL tumor cells markedly enhanced the systemic antitumor effect, including specific lymphocytes proliferation, cytotoxicity against 3LL tumor, and increased production of IFN-gamma. GM-CSF gene-modified 3LL cells significantly protected the mice from the parental 3LL tumor challenge. More importantly, the percentage of dendritic cells (DCs) in tumor site was greatly increased and the DCs differentiated into CD11c(+)CD8alpha(+) cells, which were reported to be able to benefit the induction of CD8(+) cytotoxic T lymphocytes (CTLs) that contribute to tumor regression. Our research indicated that GM-CSF could optimize the immune microenvironment in the tumor site, which provides a potent approach for immunotherapy of tumors.
DNA and Cell Biology 01/2008; 26(12):863-72. · 2.07 Impact Factor
