白花丹素调控MDSCs及胰腺癌免疫逃逸的作用机制研究

Pancreatic cancer is one of the most malignant tumors. It is the king of cancer. It is urgent to discover new drugs and treatment mechanism. The effect of Myeloid-derived suppressor cells (MDSCs) in mediating tumor immune escape, promoting tumor occurrence and development, has widely gained attention. Plumbagin (PLB) has shown potent antitumor effects in preclinical studies; however, the effect and underlying mechanism of PLB for regulation of tumor immune microenvironment, especially on MDSCs, remain unknown. CCL2 and IL-6 are important regulatory factors of MDSCs expansion, recruitment, differentiation and function. Our previous studies have shown that PLB suppress the development of pancreatic cancer and decreased the infiltration of MDSCs in tumor microenvironments. In addition, we found that the differentiation of CD33+ cells to MDSCs were suppressed by PLB, and the tumor cell expression of CCL2 and IL-6 also were inhibited by PLB. Therefore, we speculate that PLB can suppress the development of pancreatic cancer may, at least partially, through modulating MDSCs and the tumor immune environment. In this proposed study, we will investigate the role and mechanisms of PLB in the regulation of MDSCs differentiation, function and MDSCs suppression of antitumor immune cells (especially CD4 positive T cells, CD8 positive T cells, NK cells and γδT cells); investigate the therapeutic roles and mechanism of PLB in suppression of the immune escape of pancreatic cancer. These findings could provide new insights into the therapeutics of pancreatic cancer by traditional Chinese medicine.

胰腺癌恶性程度极高，是癌中之王，急需研发新的治疗药物及机制。髓系抑制性细胞（MDSCs）可抑制抗肿瘤免疫细胞活性，是介导肿瘤免疫逃逸的关键细胞，因此针对MDSCs的免疫治疗具有广阔前景。白花丹素具有抗肿瘤作用，但其对肿瘤免疫，特别是MDSCs的调控作用尚不清楚。CCL2和IL-6是调控MDSCs招募及活化的重要因子。我们体内研究证实白花丹素可抑制胰腺癌的发展，降低MDSCs的浸润；体外证实白花丹素可体外抑制CD33+细胞向MDSCs分化及CCL2和IL-6在胰腺癌细胞中的表达。因此，我们推测白花丹素可能通过调控MDSCs限制肿瘤免疫逃逸。本项目将体内外研究白花丹素调控MDSCs招募、分化和功能的作用和分子机制及其对肿瘤免疫微环境中NK、γδT、CD4及CD8阳性T细胞的促进作用，以揭示白花丹素的肿瘤免疫调节作用和细胞及分子机制，为胰腺癌临床免疫治疗开辟新途径。

胰腺癌是一类预后极差的消化系统肿瘤，已成为全球范围内死亡率最高的十大癌症之一。胰腺癌的一个显著特征是其基质成分占据了肿瘤的大部分体积。它们不仅成为了药物输送的物理障碍，其中的免疫抑制细胞如骨髓来源的抑制性细胞（MDSCs）更介导了肿瘤的免疫逃逸。因此，靶向MDSCs将成为治疗胰腺癌的有效途径。白花丹素（PLB）对多种肿瘤细胞具有明显的直接抑制作用，但是否对肿瘤免疫具有调控作用尚不明确。本研究通过构建小鼠胰腺癌原位模型，明确了PLB可以抑制小鼠胰腺原位肿瘤的进展并可以抑制肿瘤微环境中MDSCs的浸润，同时上调了肿瘤微环境中具有抗肿瘤作用的CD4+ T，CD8+ T，NKT，γδT细胞比例。通过体外研究，我们阐明了PLB通过抑制肿瘤细胞CCL2/IL-6的表达，从而抑制了MDSCs的募集和活化。PLB还可以直接抑制MDSCs的扩增分化及免疫抑制分子的产生从而解除对T细胞的免疫抑制。最后，我们进一步发现PLB能显著降低肿瘤细胞和PBMC诱导的MDSCs中p-STAT3的表达，从而阐明了PLB通过抑制胰腺癌细胞分泌CCL2和IL-6，抑制STAT3信号通路，调控肿瘤微环境中MDSCs的扩增、募集、活化和功能，从而抑制胰腺癌的发展。本研究所阐明的PLB对胰腺癌的免疫调控机制，为PLB在肿瘤治疗中的临床应用奠定了基础。