Setiadi A Francesca, Omilusik Kyla, David Muriel D, Seipp Robyn P, Hartikainen Jennifer, Gopaul Rayshad, Choi Kyung Bok, Jefferies Wilfred A
Biomedical Research Centre, Michael Smith Laboratories, Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
Cancer Res. 2008 Dec 1;68(23):9601-7. doi: 10.1158/0008-5472.CAN-07-5270.
Histone deacetylase inhibitors (HDACi) have been hailed as a powerful new class of anticancer drugs. The HDACi, trichostatin A (TSA), is thought to interfere with epigenetic control of cell cycle progression in G1 and G2-M phase, resulting in growth arrest, differentiation, or apoptosis. Here, we describe a novel mechanism of action of HDACis in promoting immune responses against tumors. We report that treatment of carcinoma cells with TSA increases the expression of many components of the antigen processing machinery, including TAP-1, TAP-2, LMP-2, and Tapasin. Consistent with this result, we found that treatment of metastatic carcinoma cells with TSA also results in an increase in MHC class I expression on the cell surface that functionally translates into an enhanced susceptibility to killing by antigen-specific CTLs. Finally, we observed that TSA treatment suppresses tumor growth and increases tap-1 promoter activity in TAP-deficient tumor cells in vivo. Intriguingly, this in vivo anti-tumoral effect of TSA is entirely mediated by an increase in immunogenicity of the tumor cells, as it does not occur in immunodeficient mice. These novel insights into the molecular mechanisms controlling tumor immune escape may help revise immunotherapeutic modalities for eradicating cancers.
组蛋白去乙酰化酶抑制剂（HDACi）被誉为一类强大的新型抗癌药物。HDACi曲古抑菌素A（TSA）被认为会干扰细胞周期在G1期和G2-M期进程的表观遗传调控，从而导致生长停滞、分化或凋亡。在此，我们描述了HDACi促进抗肿瘤免疫反应的一种新作用机制。我们报告称，用TSA处理癌细胞会增加抗原加工机制中许多成分的表达，包括TAP-1、TAP-2、LMP-2和TAP结合蛋白。与这一结果一致，我们发现用TSA处理转移性癌细胞也会导致细胞表面MHC I类分子表达增加，这在功能上转化为对抗原特异性CTL杀伤的敏感性增强。最后，我们观察到TSA处理在体内可抑制肿瘤生长并增加TAP缺陷肿瘤细胞中tap-1启动子活性。有趣的是，TSA的这种体内抗肿瘤作用完全是由肿瘤细胞免疫原性的增加介导的，因为在免疫缺陷小鼠中不会发生这种情况。这些对控制肿瘤免疫逃逸分子机制的新见解可能有助于修订根除癌症的免疫治疗方式。
