IL-24在Dectin-1-DCs诱导的Th9细胞抗肿瘤效应中的作用和机制

Interleukin (IL)-9-secreting T helper 9 (Th9) cells is a newly identified subtype of antitumor effector T cells, showing more potent antitumor efficacies than Th2, Th17 and Th1 cells in mice. Dectin-1, a C-type lectin receptor, is expressed mainly by DCs, macrophages and neutrophils. We recently found that dectin-1-activated DCs promote Th9 cell differentiation in vitro and in vivo. More importantly, dectin-1-activated DCs induced more potent antitumor effects than regular DCs in mouse tumor models. However, the mechanisms of the antitumor activities mediated by dectin-1-activated DC-primed Th9 cells remain largely unknown. Our preliminary data showed that Th9 cells primed by dectin-1-activated DCs expressed much higher levels of IL-24, granzyme B (GzmB) and IL-9 than Th9 cells primed by regular DCs. GzmB are well-characterized cytolytic factors. IL-9 is involved in the antitumor activities induced by Th9 cells in vivo. IL-24 is a unique member of the IL-10 superfamily and a tumor suppressor gene. Previous investigations showed that IL-24 displays selective cytotoxicity against tumor cells but not normal cells. Therefore, we speculate that IL-24 is a potential antitumor factor of dectin-1-activated DC-primed Th9 cells. Based on these observations, we hypothesize that dectin-1-activated DC-primed Th9 cells exert their superior antitumor effects through upregulation of IL-24, GzmB and IL-9. This application is aimed to explore the mechanisms underlying the antitumor effects by dectin1-activated DC-primed Th9 cells and their clinical significance. In this project, we will verify the upregulation of IL-24, GzmB and IL-9 in dectin-1-activated DC-primed Th9 cells. We will clarify the role of IL-24, GzmB and IL-9, especially IL-24, in the antitumor effects induced by dectin-1-activated DC-primed Th9 cells in vitro and in vivo. This project will help us better understand the molecular properties of dectin-1-activated DC-primed Th9 cells and the mechanisms underlying their antitumor abilities, and may have important clinical significance.

Th9细胞是新近发现的具有抗肿瘤效应的Th细胞亚群。我们最近研究发现dectin-1活化的树突状细胞（dectin-1-DCs）促进Th9生成，且体内诱导很强的肿瘤治疗效应。然而，我们对dectin-1-DCs诱导Th9的抗肿瘤效应机制还不清楚。我们前期初步研究发现dectin-1-DCs诱导的Th9高表达IL-9、IL-24和GzmB等因子。IL-9和GzmB是已知抗肿瘤效应分子，而IL-24是抑癌基因，是潜在的抗肿瘤效应分子。据此，我们假设dectin-1-DCs诱导的Th9通过表达IL-24、GzmB和IL-9从而发挥强有力的抗肿瘤效应。通过本研究，申请者将阐明IL-24等效应分子在Th9抗肿瘤中的作用；阐明Dectin-1-DCs促进Th9表达IL-24的分子机制，具有重要的理论意义和潜在的临床应用前景。

T细胞过继治疗是一种很有前途的肿瘤治疗方法。Th9是一新型具有优异抗肿瘤潜能的效应T细胞。然而，Th9的抗肿瘤效应机制仍需进一步阐明。我们发现Th9除了高表达IL-9外，也表达分泌大量的IL-24。IL-24是IL-10家族成员，有胞内和分泌型二种形式。细胞内IL-24是抑癌基因，可直接介导肿瘤细胞凋亡。有研究提示分泌型IL-24也具有抗肿瘤潜能。据此，我们假设Th9通过高表达IL-24介导产生强有力的抗肿瘤效应。通过本研究，我们发现IL-24抑制Th9细胞增殖和凋亡。而缺失IL-24的Th9细胞抗肿瘤效应明显降低。该项目阐明了 IL-24 在 Th9细胞抗肿瘤效应中的作用及机制，包括：1） IL-24 体外对Th9 自身的分裂增殖和存活及其抗肿瘤活性的影响； 2）Th9分泌的 IL-24 对肿瘤细胞的细胞毒活性，以及对肿瘤细胞分裂增生能力的影响； 3）IL-24 对Th9细胞体内抗肿瘤活性的作用；4）转录因子Foxo1在分泌IL-24的Th9抗肿瘤中的作用。该项目揭示表达IL-24的Th9 细胞的抗肿瘤效应及机制，为其临床应用提供理论依据和临床前期数据，具有重要的理论意义和应用价值。