肿瘤微环境驱动肿瘤发生发展，肝癌是典型的炎症相关性肿瘤，其炎症微环境可诱导肝癌细胞高表达免疫检查点分子PD-L1和CD47，促进肝癌免疫逃逸。我们前期研究发现：经历炎症刺激的肝癌细胞静息一定时间后，再次接受炎症刺激，其表达PD-L1和CD47分子的水平比初次刺激时更高，表达速度也更快，表现出对炎症刺激具有记忆性。结合固有免疫细胞和某些上皮干细胞或祖细胞的记忆机制的最新研究，我们提出研究假说：肝癌细胞通过对炎症环境促其表达PD-L1和CD47分子的记忆，获得更强免疫逃逸能力；肝癌细胞中的PD-L1和CD47基因调控区的潜伏增强子是记忆产生的机制。本项目将揭示炎症促肝癌免疫逃逸的新机制，为建立靶向免疫逃逸的肿瘤治疗方案提供新思路和新靶点；同时将首次论证炎症微环境对肿瘤的驱动效应可以通过肿瘤细胞记忆的形式在肿瘤演化中得以累积，这将补充和丰富目前的肿瘤学理论体系，并有望开拓新的肿瘤研究领域。

Genome instability and tumor environment drive the tumor evolution. The former contributes to accumulation of gene mutation in malignant cells so that the tumor evolution proceeds. The latter can impact malignant behaviors by interaction with the tumor cells. However, whether the impaction can be accumulated in the tumor cells is not known so far.. PD-L1 and CD47 are critical immune checkpoint molecules mediating cancer immune escape. The PD-L1 molecules are referred to as B7-H1 or CD274 molecules. Its expression is frequently found on a variety of cancer cells. The PD-L1 molecules expressed on the cancer cells can engage its receptors PD-1 expressed on the surface of cancer-specific CTL, leading to exhaustion or apoptosis of the CTL. The CD47 molecules are expressed usually on various cancer cells at a high level. The CD47 molecules expressed on cancer cells can engage its receptor SIPRα expressed on the surface of macrophages, contributing to inhibition of the macrophage-mediated phagocytosis of the cancer cell. . Hepatocellular carcinomas (HCC) are prototypical inflammation-related cancers with inflammatory environment consisted of tumor-associated macrophages and its secreted cytokines such as IL-1, TNF-α and IL-6. The inflammatory environment can induce the expression of PD-L1 and CD47 in the HCC cells. Our previous studies showed that activated macrophages promote expression of PD-L1 and CD47 in HCC cells. Surprisingly, we found that the second inflammatory stimulation induced the expression of PD-L1 and CD47 more strongly and rapidly compared to the first stimulation when the HCC cells were subjected to twice inflammatory stimulations with a long interval. Considered memory of infection or inflammation in innate immune cells or some epithelial stem or progenitor cells, we speculate that the HCC cells may have memory of induction of PD-L1 and CD47 expression by the inflammatory environment. The memory of inflammatory stimulation in HCC cells will lead to robust immune evasion. In addition, the memory mechanism may be latent enhancers associated with PD-L1 or CD47 expression in the HCC cells. Therefore, the hypothesis is proposed that HCC cell have memory of immune escape promoted by HCC inflammatory environment. . In the present project, we will confirm our preliminary finding that HCC cells can memorize the inflammatory stimulation to express PD-L1 and CD47 at higher level. Then, we will clarify the molecular mechanism underlying the memory of inflammatory stimulation in HCC cells. Lastly, we will perform in vivo and in vitro experiments to show that the memory of enhanced expression of PD-L1 and CD47 in HCC cells will lead to robust immune evasion.. Our expected results will reveal a new mechanism of HCC immune evasion and provide new ideas and new targets for establishment of novel immunotherapies targeting immune evasion. Moreover, our study will provide data for the first time to argue that the impact of tumor environment may be accumulated through cellular memory in malignant cells during tumor evolution. These findings will improve the oncologic theory and initiate a new research field in oncology.