HDAC1抑制剂Romidespin活化肺癌细胞NF-κB信号通路促进T细胞抗肿瘤的机制研究

The demonstrated role of cancer "immunoediting" in selecting tumor cells best suited to escape immune attack provides additional evidence of a key function of the immune system in controlling cancer. Recent immunotherapy strategies to enhance tumor antigenicity and boost T cell-induced responses against solid tumors have shown considerable promise to reverse immunoediting. Based on our study, activated IKKβ increases antigen peptides onto lung cancer cell surface, promoting the secretion of cytokines (CCL2 and CCL5) those recruitment CD8+ T cell, in result of enhancing antitumor responses in OT-1 mouse model. Romidepsin promotes cancer cell IKKβ activation, enhanced CCL5 expression, suggesting that by NF-kB signaling pathway enhanced T cell-induced antitumor effect. To further investigate the reversal of immune editing that Romidespin promote CD8 + T cells specifically recognize and molecular mechanisms of killing lung cancer cells, we intend to conduct the following studies: 1) Romidepsin promotes cancer antigenicity by activating NF-κB pathway; 2) Romidepsin possible mechanism to promote cancer cell IKKβ activation and increased expression of CCL5 (with or without NF-κB other molecular pathways involved in); 3) Romidepsin promotes antigen peptide expression, presenting depend on HDAC inhibition? This study is expected to explore corresponding molecular mechanisms that Romidepsin affect lung cancer cells by T cell-mediated immune surveillance. These studies are helpful for providing new clues for acknowledging reversal of immunoediting in lung cancer immunotherapy.

免疫编辑是肿瘤免疫逃逸的重要原因。近年研究显示，提高肿瘤免疫原性、改变肿瘤免疫抑制微环境，增强效应性T细胞功能有望逆转肿瘤免疫逃逸。我们前期研究发现，OT-1小鼠模型NF-κB激活增加肺癌表面的抗原肽表达、促进趋化细胞因子分泌，募集CD8+T细胞清除肿瘤。我们还发现HDAC1抑制剂Romidepsin可促进IKKβ活化、上调CCL5表达，推测Romidepsin可能通过活化NF-κB信号通路，增强T细胞介导的抗肿瘤作用。为了进一步探讨Romidepsin的作用机制，本课题拟进行如下研究：1）Romidespin激活NF-κB通路促进抗原肽表达内在机制；2）Romidepsin促进肺癌细胞IKKβ活化和CCL5表达增高的可能机制；3）Romidepsin促进抗原肽表达是否依赖于HDAC1。本研究有望了解Romidepsin促进效应性T细胞抗肿瘤的功能的分子机制，为肺癌免疫治疗提供新思路。

免疫编辑是肿瘤免疫逃逸的重要原因。提高肿瘤免疫原性、改变肿瘤免疫抑制微环境，增强效应性T细胞功能有望逆转肿瘤免疫逃逸。以NF-κB下游的T细胞相关的基因CCL5等为研究对象，筛选出上调CCL5化疗药物，有目的研究Romidepsin增加了肺癌细胞膜上表达具有免疫原性OVA多肽，从而逆转免疫编辑促进CD8+T细胞特异性识别和杀伤肺癌细胞，同时促进了肺癌细胞CCL2和CCL5表达增高。我们还发现HDAC1抑制剂Romidepsin可促进IKKβ活化、上调CCL5表达，推测Romidepsin可能通过活化NF-κB信号通路，增强T细胞介导的抗肿瘤作用。1）发现Romidepsin在移植瘤体内促进CD8+T细胞杀伤功能，上调IKKβ，促进CCL5等趋化因子分泌， 探索促进T细胞抗肿瘤的相关机制；2）探讨Romidepsin通过抑制HDAC促抗原表达及递呈的作用具有IKKβ依赖性的分子机制，提出新的治疗思路。Romidepsin促进效应性T细胞抗肿瘤的功能的分子机制，为肺癌免疫治疗提供新思路。