IL-33/ST2通路调控CD8+T和免疫抑制相关细胞的功能抗软组织肉瘤的作用和机制

Cancer immunotherapy is a promising new strategy for soft tissue sarcoma (STS) treatment. IL-33 is a candidate cytokine for STS immunotherapy which can activate T lymphocytes. However, the expression and role of IL-33 in STS is poorly understood. In our previous study, we found that the expression of IL-33 and its receptor ST2 was decreased in STS. By analyzing sarcoma data from The Cancer Genome Atlas (TCGA), we found that higher transcriptional levels of IL-33 and ST2 were associated with a favorable outcome, indicating that IL-33/ST2 axis plays an anti-tumor role in STS, but the specific mechanism remains unclear. Moreover, we found that both the expression of IL-33 and ST2 were positive correlated with that of CD8A, IFN-γ, and chemokines which recruit CD8+ T cells. We also found that the expression of IL-33 was negatively related to that of TGF-β1 and chemokines which recruit regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Thus, we speculate that the IL-33/ST2 axis may play an anti-tumor role in STS through recruiting CD8+ T cells and promoting the secretion of IFN-γ, and antagonizing Tregs and MDSCs-mediated immunosuppression. In this study, we will further investigate the expression and prognostic significance of IL-33/ST2 in STS. We will knock down and overexpress IL-33, and combine cell co-culture and ST2-/- mice tumorigenesis experiments, to explore the anti-sarcoma immune mechanism of IL-33/ST2 pathway. Our study will establish IL-33 as a useful prognostic biomarker and a potential immunotherapeutic target for STS.

免疫治疗是软组织肉瘤治疗的新希望。IL-33是能活化T细胞的细胞因子，有望用于肉瘤免疫治疗，但其在肉瘤中的表达和功能未明。我们前期发现，IL-33和受体ST2在肉瘤中表达下降；分析TCGA的数据发现，IL-33和ST2表达高的肉瘤患者预后更好，表明IL-33/ST2发挥抗肉瘤作用，但机制未明。我们发现IL-33/ST2与CD8A、IFN-γ及募集CD8+T细胞的趋化因子的表达正相关，与TGF-β1及募集Tregs、MDSCs的趋化因子的表达负相关，据此我们推测IL-33/ST2通路可募集和促进CD8+T细胞分泌IFN-γ，并拮抗Tregs、MDSCs介导的免疫抑制来发挥抗肉瘤作用。本项目拟进一步研究IL-33/ST2的表达与肉瘤预后的关系；分别敲低和过表达IL-33，结合细胞共培养和ST2-/-小鼠成瘤实验等，探讨IL-33/ST2通路抗肉瘤的免疫机制，为肉瘤的免疫治疗和预后提供新靶标。

目前，晚期软组织肉瘤的治疗选择有限，免疫治疗给软组织肉瘤治疗带来了新希望。IL-33是免疫治疗的潜在靶点，它对肿瘤微环境具有复杂的调控作用，但其在肉瘤中的表达和功能尚未阐明。通过本项目研究：①明确了IL-33和ST2在纤维母细胞肿瘤（或称纤维肉瘤，软组织肉瘤的一类亚型）中的表达特征，IL-33/ST2通路与CD8A和FoxP3阳性细胞及免疫检查点TIM3、PDL1的表达之间具有广泛的相关性，而CD8A和FoxP3阳性细胞的增加和PDL1的表达又和肿瘤的恶性进展相关，提示IL-33/ST2通路可能通过上调CD8+ T和FoxP3+ Tregs细胞中免疫检查点的表达，使其处于免疫抑制状态。②建立了过表达多种形式IL-33的HT1080人纤维肉瘤细胞株，发现分泌型IL-33对HT1080细胞的增殖与迁移具有一定的促进作用，表明肿瘤细胞来源的IL-33可能通过自分泌和旁分泌作用，促进肿瘤细胞的增殖和迁移。③揭示了肿瘤细胞分泌IL-33的机制：在肿瘤微环境中，炎症介质如TNF-α可通过激活NF-κB及MAPK信号通路，诱导IL-33表达升高，并由核转移到胞浆，然后（至少部分）通过分泌型溶酶体分泌到胞外。综上可推测，肿瘤细胞可被微环境中的炎症介质等诱导表达并分泌IL-33，一方面作用于肿瘤浸润T细胞（TILs）如CD8+ T和Tregs等，上调免疫检查点如TIM3、PDL1的在这些细胞上的表达，使其处于免疫抑制状态，从而帮助肿瘤免疫逃逸；另一方面，分泌的IL-33也可作用于肿瘤细胞自身，促进其增殖和迁移，最终促进纤维母细胞肿瘤的进展。以上研究结果提示，具有IL-33高表达、TILs密度增多及PDL1和TIM3高表达特征的肿瘤患者，可能受益于IL-33抗体及PDL1和TIM3抑制剂的联合治疗，本研究为肿瘤患者的免疫治疗提供了新策略和理论依据。