干扰素α重塑肿瘤微环境增强PD-1抗体治疗肝癌的免疫效应机制研究

The previous studies of our research team found that interferon-alpha could effectively inhibit the growth and metastasis of hepatocellular carcinoma (HCC) in mice, and its efficacy had been verified in clinical randomized controlled trials. However, HCC may be resistant to interferon-alpha therapy in the later treatment. How to screen which patients are suitable for interferon-alpha therapy or to combine new interventions based on existing treatment methods is the key to further improve the efficacy of interferon-alpha in the treatment of HCC. In the previous work, we found that interferon-alpha caused a significant decrease in the proportion of M2 macrophages and increase in the proportion of M1 macrophages, and significantly increased the expression of PD-L1 in HCC. So far, the researches of interferon-alpha in HCC immunity has not been reported yet. This study intends to simulate the in vitro and in vivo model of HCC immune microenvironment, further clarify the relationship between interferon-alpha and HCC microenvironment and its effect on metastasis of HCC. Meanwhile, the present study will explore the effect of interferon-alpha therapy combined with PD-1 antibody to further improve the efficacy of interferon-alpha in the treatment of HCC based on pre-clinical animal experiments.

课题组前期研究发现干扰素α可有效抑制小鼠肝癌的生长和转移复发，其疗效亦在临床随机对照研究中得到验证。然而，在治疗后期，肝癌可能对干扰素α产生耐药。如何筛选哪些患者适合干扰素α治疗或者在现有治疗方法基础上联合新的干预手段是进一步提高干扰素α治疗肝癌疗效的关键。前期工作中，我们发现干扰素α引起肝癌免疫微环境中M2型巨噬细胞比例明显减少，M1型巨噬细胞比例明显增加，肝癌PD-L1表达明显增强。迄今，干扰素α在肝癌肿瘤免疫方面的研究目前尚未见报道，在此基础上，本课题拟模拟人肝癌免疫微环境建立体内外模型，进一步明确干扰素α与肝癌免疫微环境的关系及其对肝癌侵袭转移的影响，同时结合临床前动物实验，以期探寻基于干扰素α联合PD-1抗体的免疫疗法进一步提高干扰素α治疗肝癌的疗效。

课题组前期研究发现干扰素α可有效抑制小鼠肝癌的生长和转移复发，其疗效亦在临床随机对照研究中得到验证。然而，在治疗后期，肝癌可能对干扰素α产生耐药。如何筛选哪些患者适合干扰素α治疗或者在现有治疗方法基础上联合新的干预手段是进一步提高干扰素α治疗肝癌疗效的关键。干扰素α用于抗病毒及抗肿瘤细胞毒性药物在临床已开展应用，但如何提高疗效及与免疫治疗的联合应用尚无涉足。本项目研究发现，干扰素α可以促进通过上调肝癌CCL4分泌，继而促进杀伤性CD8+T细胞的浸润。另一方面，长期应用干扰素α却能通过JAK1-STAT3上调杀伤性CD8+T细胞免疫抑制分子PD-1，其细胞因子分泌能力显著下降继而诱导免疫耗竭。而在皮下瘤模型以及原位肿瘤模型中，联合治疗能够更加有效地抑制肿瘤的生长，延长了原位肿瘤模型小鼠的生存期，提示PD-1抑制剂联合干扰素α通过协同作用发挥更大的治疗效果。以上研究不仅探索了干扰素α对肝癌免疫微环境中CD8+T细胞的调节作用，而且揭示了肝癌联合免疫治疗的新机制及新策略，具有较高的转化价值。