阿可拉定对肝癌髓外造血产生MDSC的影响和调控机制

Cancer is associated with a profound perturbation in myelopoiesis that results in myeloid biased response to promote disease progression. Recent studies in our labs suggest that tumor induced a heightened splenic myelopoiesis, and the hematopoietic stem/progenitor cells (HSPCs) were recruited and “primed” to generate immunosuppressive myeloid cells (MDSC) with stronger inhibitory function, which in turn promoted cancer progression and influenced the response of treatment. Icaritin (ICT) is a potential new antitumor immunomodulatory drug, but its exact mechanisms are not fully understood. We recently found that ICT can significantly down-regulate the number and percentage of MDSCs in the spleen and the expression of STAT3 and Arginase-1 from MDSCs in the tumor, and up-regulate the percentage of IFN-γ+ CTLs in the tumor for inhibiting the progress of HCC. Based on those observations, we will carry out experimental studies to: 1). Determine the anti-tumor effect of ICT in a variety of HCC models. 2). Examine the effects of ICT on the composition and function of hematopoietic stem/progenitor cell subsets in the spleen, reveal the effects and mechanisms of ICT on the regulation of the extramedullary hematopoiesis in spleen. 3). Investigate the effect and mechanism of ICT on the response to the treatment of α-PD-L1, α-PD-1 and sorafenib. 4). Identify the biomarkers that can be used to evaluate the effect of ICT treatment response. The results obtained from this project will explore the scientific and theoretical basis for the regulation of extramedullary hematopoiesis as a new strategy.

肿瘤能引起宿主造血活动异常产生髓系偏移来促进疾病进展。我们新近发现：肿瘤可诱导脾脏髓外造血功能，通过招募并“重编程”造血干/前体细胞来产生具有更强抑制功能的MDSC，进而调控肿瘤进展和对治疗的应答。阿可拉定是一种新型抗肿瘤免疫调节药物，其确切机制尚不完全清楚。前期结果表明：阿可拉定显著下调脾脏中MDSC数量和比例以及肿瘤中MDSC表达STAT3和Arginase-1，上调肿瘤中IFN-γ+ CTLs，从而抑制肝癌进展。以此为基础，本课题拟结合体内外实验，在多种肝癌模型中进一步明确阿可拉定的抗肿瘤作用，探讨其对脾脏造血干/前体细胞组成和功能的影响，揭示其调控肝癌相关脾脏髓外造血的作用靶点及信号通路，并阐明该过程抗PD-L1、抗PD-1及sorafenib治疗应答的效果及机制，鉴定其治疗效果的生物标记物。所得的结果为肝癌的治疗提供参考，也为探讨以调控髓外造血为靶标的新型肝癌治疗方案提供理论基础

近年来的研究表明，脾髓外造血(EMH)是髓源性抑制细胞(MDSCs)在肿瘤组织中积累的重要机制，从而促进了疾病的进展。阿可拉定是淫羊藿属植物的一种戊烯类黄酮衍生物，被认为是一种新的免疫调节剂，可以延长肝细胞癌(HCC)患者的生存期。然而，阿可拉定的抗肿瘤作用是否通过调控髓外造血产生的MDSCs来实现尚不清楚。在此，我们研究了阿可拉定在小鼠肝癌中的抗肿瘤潜力及其作用机制。阿可拉定抑制肿瘤进展，并显著延长小鼠原位和皮下肝癌肿瘤的生存期。阿可拉定并不是直接对肿瘤细胞发挥其细胞毒作用抗肿瘤，而是显著降低肿瘤和脾脏MDSCs的积累和活化，增加细胞毒T细胞的数量和活性。在机制上，阿可拉定下调肿瘤相关的脾髓外造血，从而减少MDSCs的生成和激活。用脐带血来源的造血前体进行短期培养，验证了阿可拉定对体外培养的人MDSCs的抑制作用。此外，阿可拉定可协同增强免疫检查点阻断治疗肝癌小鼠的疗效。这些结果表明，阿可拉定通过抑制脾髓外造血而抑制MDSCs的产生，从而抑制肿瘤免疫抑制，进而引发抗肿瘤免疫应答。因此，阿可拉定可以作为一种新型的辅助药物，甚至可以作为一种独立的治疗药物，有效地治疗肝癌。