IFNγ调控内皮细胞糖酵解影响肺癌化疗的机制研究

Chemotherapy is the main treatment for lung cancer. The penetration of chemotherapeutic drug to each tumor cell through the tumor micro-circulation, is important for the ideal outcome. Chemotherapy inevitably induces necrosis and inflammation. However, whether the modulation of inflammatory cytokines could be explored to refine the tumor micro-circulation and improve drug delivery has not been fully understood. My previous studies found that: IFNγ disrupts endothelial junction through inhibition of Dll4; IFNγ affects cellular metabolism via inhibiting AMPK; transient neutralizing IFNγ could reduce tumor metastasis during chemotherapy. Therefore, I hypothesize that IFNγ modulates endothelial metabolism and integrity, which affects drug penetration into tumor. Using mouse lung cancer model, this project will study: 1) the regulation of endothelial glycolysis by IFNγ and the underlying mechanism; 2) the impact of neutralizing IFNγ on tumor endothelial integrity and vascular perfusion; 3) tumor immune microenvironment; 4) drug delivery of cisplatin and tumor inhibition. The findings of this project will conduce to the design of novel adjuvant chemotherapy for cancer through targeting tumor micro-circulation, and will be instrumental for the understanding of the tumor immune effective mechanisms.

化疗是肺癌的重要治疗手段之一,化疗药通过肿瘤血管微循环充分渗透到瘤内对于肿瘤化疗至关重要。肿瘤化疗过程往往伴随坏死和炎症，可否通过调控炎症因子改善肿瘤微循环、增强化疗药物渗透尚不完全清楚。我的研究发现：炎症因子IFNγ抑制血管内皮细胞Dll4信号通路，破坏细胞间连接；调节AMPK，影响细胞代谢；化疗过程中，一过性中和IFNγ可减少肿瘤细胞转移。据此，我假设IFNγ调控内皮细胞代谢和各细胞间的连接会影响化疗药物的瘤内递送。本项目拟以小鼠肺癌为模型研究：1）IFNγ对内皮细胞代谢的调节作用及其分子机制；2）中和IFNγ对血管内皮细胞间连接和组织灌注的调节；3）对肿瘤免疫微环境的影响；和4）对化疗药顺铂瘤内渗透及药效的影响。研究成果将有助于设计针对肿瘤血管的化疗辅助方案，并加深我们对肿瘤免疫效应机制的理解。

肿瘤血管微循环对肿瘤微环境发挥重要的调控作用，影响肿瘤的化疗疗效。有效的肿瘤化疗依赖于化疗药物的局部组织渗透以及抗肿瘤免疫的激活。本项目主要研究了炎症因子IFNγ调控肿瘤内皮细胞代谢的分子机制，揭示了血管内皮细胞间连接的调控机制及对肿瘤免疫反应的影响，探索了靶向IFNγ改善肿瘤血管微循环，提高肿瘤化疗疗效的治疗策略。研究发现：① IFNγ通过上调内皮细胞糖酵解，产生更多乳酸，导致VE-cadherin内吞，破坏肿瘤血管完整性，而中和IFNγ限制乳酸的过量生成促进化疗药的递送，增强化疗效果。②中和IFNγ显著降低化疗药诱导的心肌毒性。③S100A4通过调控记忆性CD8+ T细胞代谢抑制其IFNγ的表达，促进炎症进展。④紧密连接蛋白CLDN12介导MDSC细胞穿过肿瘤血管抑制抗肿瘤免疫反应。⑤ ZIP1+成纤维细胞通过传递Zn2+给肺癌细胞导致化疗抵抗。⑥通过单细胞测序检测到肝癌异质性并筛选到与预后相关的基因特征。本项目的这些发现为肿瘤的防治提供了新的理论基础和治疗策略。