白介素15对脑胶质瘤微环境中髓源抑制细胞的功能重塑及分子机制

Malignant gliomas are the most common primary intracranial tumor, with a proclivity for widespread invasion and rampant destruction of the surrounding brain tissue. This infiltrative process affords gliomas protection from traditional therapies and associates with highly recurrent high, morbidity, and mortality. With the rapid development of immunotherapy in non-CNS tumors, the development of effective new immunotherapy strategies for glioma is urgently needed. Immune suppression of tumor microenvironment is one of the major obstacles that currently limit the efficacy of immunotherapy for patients with glioma. In our previous study, IL-15 as a vaccine adjuvant combined with tumor vaccine, show an excellent effect to glioma than immunization with vaccine alone. Further studies revealed that IL-15 can significantly reduce the myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, reverse the immunosuppressive function, but the mechanism is unclear. Based on our previous results, we will focus on the mechanisms of the regulation of IL-15 on MDSC. The contents in our experiment includes 3 aspects as fellow: 1) the association of MDSC with tumor invasion and malignant degree in patients with glioma; 2) the association of MDSC infiltration with survival in patients with glioma; 3) the role of MDSC to proliferation and differentiation, and to the expression of immune suppression factor in MDSC after intervention by IL-15. The study will explain that preliminary reversal mechanism of immunosuppression resulted by MDSC after IL-15 treatment, and offer new and potential strategies and methods for the treatment of glioma.

恶性脑胶质瘤因侵袭性生长，极易复发，致残率和死亡率高。随着免疫治疗在其它肿瘤的迅猛发展，发展胶质瘤免疫治疗被寄予厚望。微环境中免疫抑制性细胞是目前限制免疫治疗疗效的主要障碍之一。项目组前期发现将IL-15用作胶质瘤疫苗佐剂，显著提高了疫苗的疗效。进一步研究发现脑胶质瘤组织中大量髓源抑制性细胞(MDSC)侵润，而IL-15可以显著降低MDSC对肿瘤的浸润，但机制不清。本项目以此为基础，重点研究IL-15对MDSC功能调控的分子机制，主要包括：1)临床脑胶质瘤样本中MDSC浸润特点与肿瘤恶性程度关系；2）脑胶质瘤样本中MDSC浸润与患者预后的关系；3)IL-15对MDSC增殖、分化及关键信号通路主要表达的免疫抑制因子的影响。本研究将为阐释IL-15对MDSC的免疫抑制状态的逆转机制提供前期基础，为脑胶质瘤的治疗提供新的策略和方法。

恶性脑胶质瘤因侵袭性生长，极易复发，致残率和死亡率高。随着免疫治疗在其它肿瘤的迅猛发展，研究胶质瘤免疫治疗被寄予厚望。胶质瘤微环境中免疫抑制性细胞是目前限制免疫治疗疗效的主要障碍之一。项目组前期发现将IL-15用作胶质瘤疫苗佐剂，显著提高了疫苗的疗效。进一步研究发现脑胶质瘤组织中大量髓源抑制性细胞(MDSC)侵润，经IL-15干预后，显著降低MDSC对肿瘤的浸润，但机制不清。本项目以此为基础，重点研究IL-15对MDSC功能调控的分子机制，主要包括：1)临床脑胶质瘤样本中MDSC浸润特点与肿瘤恶性程度关系：结果发现MDSC在不同级别胶质瘤中均能检测到，但数量差异较明显，高级别胶质瘤明显多于低级别胶质瘤，按照IV、III、II、I级递减；此外，MDSC在瘤脑平面仍能被检测到，随肿瘤细胞侵润而伴随分布，肿瘤级别越低侵润数量越少；2）脑胶质瘤样本中MDSC浸润与患者预后的关系：MDSC的数量与患者的预后呈正相关，高级别胶质瘤中MDSC数量少于低级别胶质瘤，前者预后较后者明显降低；3) IL-15对MDSC增殖、分化及关键信号通路主要表达的免疫抑制因子的影响 结果发现IL-15能够抑制MDSC的生物学功能，抑制后者增殖、促进分化，并减少肿瘤微环境中免疫抑制因子如IL-6、IL-10、TGF-β，ARG-1等的释放，从而改善了微环境中的免疫抑制状态。本研究发现了胶质瘤微环境中的MDSC的分布特点与变化规律，证实了IL-15对MDSC的免疫抑制状态的逆转作用，同时阐释了IL-15对MDSC的免疫抑制状态的其逆转的部分机制，为脑胶质瘤的免疫治疗提供了新的策略思路和方法。