3月17日讯 /生物谷BIOON/ --近日，来自中国科学院上海健康科学研究所的时玉舫研究员在著名国际期刊oncogene在线发表了他们关于抗肿瘤免疫应答的最新研究进展。他们通过研究发现利用组蛋白去乙酰化酶抑制剂(HDACI)抑制CD4+T细胞激活诱导的细胞死亡（AICD）过程能够有效增强抗肿瘤免疫应答过程，对于利用免疫应答治疗肿瘤具有重要意义。研究人员指出，体内抗肿瘤免疫应答的低效性部分源于T细胞不能对肿瘤产生有效应答。，而发生在T细胞上的FAS-FASL依赖性的激活诱导型细胞死亡（AICD）被认为是抗肿瘤免疫应答低下的一个主要因素。目前关于AICD的分子机制已经了解的非常清楚，但能否通过调控AICD过程治疗癌症仍有待探讨。在这项研究中，研究人员发现组蛋白去乙酰化酶抑制剂（HDACI）能够抑制肿瘤内CD4+T细胞凋亡，增强抗肿瘤免疫应答，抑制黑色素瘤生长。这种抑制效应能够通过抑制激活型CD4+T细胞内NFAT1调控的FASL表达特异靶向AICD过程。研究人员利用携带FASL突变的gld/gld小鼠模型进行研究发现HDACI不能有效抑制浸润性CD4+T细胞的AICD过程，证明对FASL的调控在HDACI的抗肿瘤效应中具有重要作用。研究人员通过研究进一步发现HDACI和anti-CTLA4的联合作用能够进一步增强CD4+T细胞的浸润性，达到协同抑制肿瘤发展的治疗效果。综上所述，这些结果表明利用HDACI调节肿瘤浸润性CD4+T细胞AICD过程能够增强抗肿瘤免疫应答，揭示了HDACI发挥抗肿瘤效应的一个新的分子机制。（生物谷）本文系生物谷原创编译整理。欢迎转载！转载请注明来源并附原文链接。更多资讯请下载。Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunityK Cao, G Wang, W Li, L Zhang, R Wang, Y Huang, L Du, J Jiang, C Wu, X He, A I Roberts, F Li, A B Rabson, Y Wang and Y ShiThe poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL-dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can inhibit apoptosis of CD4+ T cells within the tumor, thereby enhancing anti-tumor immune responses and suppressing melanoma growth. This inhibitory effect is specific for AICD through suppressing NFAT1-regulated FasL expression on activated CD4+ T cells. In gld/gld mice with mutation in FasL, the beneficial effect of HDACIs on AICD of infiltrating CD4+ T cells is not seen, confirming the critical role of FasL regulation in the anti-tumor effect of HDACIs. Importantly, we found that the co-administration of HDACIs and anti-CTLA4 could further enhance the infiltration of CD4+ T cells and achieve a synergistic therapeutic effect on tumor. Therefore, our study demonstrates that the modulation of AICD of tumor-infiltrating CD4+T cells using HDACIs can enhance anti-tumor immune responses, uncovering a novel mechanism underlying the anti-tumor effect of HDACIs.
