Department of Immunology, Shanghai Medical College, Key Laboratory of Molecular Medicine of Ministry of Education, Fudan University, China.
Cell Mol Immunol. 2011 Jul;8(4):359-67. doi: 10.1038/cmi.2011.12. Epub 2011 May 16.
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.
天花粉蛋白（TCS）从中药瓜蒌中提取，已显示出抑制肿瘤生长的潜力。然而，其对肿瘤-宿主相互作用的免疫调节作用尚不清楚。在这项研究中，我们专注于 TCS 对 3LL 刘易斯肺癌肿瘤模型中鼠抗肿瘤免疫反应的影响，并探讨了可能涉及的分子途径。除了抑制 3LL 肿瘤细胞的增殖和诱导其凋亡外，TCS 在免疫功能正常的 C57BL/6 小鼠中比在裸鼠中更显著地延缓肿瘤生长并延长小鼠存活时间。这反映了宿主免疫系统参与肿瘤消除的事实。通过 FACS 分析，我们发现 TCS 增加了效应 T 细胞的百分比，特别是来自荷瘤小鼠的干扰素-γ（IFN-γ）产生的 CD4（+）和 CD8（+）T 细胞。TCS 还促进了抗原特异性效应 T 细胞的剧烈增殖，显著增加了 Th1 细胞因子的分泌，并在荷瘤小鼠中引发了更多的记忆 T 细胞，从而增强了抗肿瘤反应并诱导了免疫保护。此外，我们发现 TCS 上调了 3LL 肿瘤细胞中肺癌 1 肿瘤抑制因子（TSLC1）的表达及其配体，I 类限制的 T 细胞相关分子（CRTAM）在效应 T 细胞中的表达。用小干扰 RNA（siRNA）阻断 TSLC1 表达显著消除了 TCS 对效应 T 细胞增殖和细胞因子分泌的影响，表明 TCS 通过增强 TSLC1 与 CRTAM 之间的相互作用至少部分增强了抗肿瘤免疫反应。总的来说，我们的数据表明 TCS 不仅直接影响肿瘤细胞，还通过 TSLC1 和 CRTAM 之间的相互作用增强抗肿瘤免疫。这些发现可能导致肿瘤消退的新方法的发展。
