TL1A诱导的Tc9细胞的抗肿瘤效应和机制及其在多发性骨髓瘤免疫治疗中的应用

Multiple Myeloma (MM) is the second most common hematologic malignancy. MM still remains incurable despite much progress has been made in the treatment of the disease. Clearly, there is an urgent need for developing new approaches for the treatment of MM. Adoptive T-cell immunotherapy is a promising approach for tumor immunotherapy. However, clinical trials of tumor adoptive T-cell immunotherapy have only yielded limited clinical benefits. The main challenge is to identify more potent antitumor effector T cells. Tumor-specific Tc1 cells are the major effector cells used in adoptive tumor immunotherapy. Interleukin (IL)-9-secreting Tc9 cells are a newly identified Tc cell subtype, showing more potent antitumor efficacies than Tc1 cells in mice. Our preliminary data show that the addition of the TNF-like ligand 1A (TL1A) during Tc9 cell differentiation potently enhances the induction of Tc9 cells. However, the role and capacity of TL1A-induced Tc9 cells (TL1A-Tc9) in tumor immunotherapy, including MM, remains unknown. We also found that TL1A-Tc9 cells express high levels of not only IL-9 but also IL-24. IL-9 is a T-cell growth factor, and does not exhibit direct cytotoxicity against tumor cells. IL-24 is a unique member of the IL-10 superfamily, displaying endogenous and secreted forms. Endogenous IL-24 is a tumor suppressor and is well known for its apoptotic effect in cancer cells while having no such effect on normal cells. Recent reports showed that secreted IL-24 can also induce tumor cell apoptosis. Interestingly, our preliminary data showed that culture supernatants from TL1A-Tc9 cells exhibits inhibitory effects on tumor cell proliferation. Based on these observations, we hypothesize that TL1A-Tc9 cells exert their superior antitumor effects through the production of IL-24. The goal of this work is to determine the role and the mechanisms of IL-24 in TL1A-Tc9-induced antitumor immunity. We will explore the characteristics of TL1A-Tc9 cells and verify TL1A-Tc9 cell expression of IL-24. We will explore the antitumor activities induced by tumor specific TL1A-Tc9 cells depends on the expression of IL-24. Finally, we will examine the capability of TL1A-Tc9 cells in the therapy of 5TGM1 MM in the C57BL/KALW mouse model. This project will help us better understand the antitumor efficacy of IL-24-expressing TL1A-Tc9 cells and the underlying mechanisms and may have important clinical significance.

多发性骨髓瘤（MM）目前难以治愈，迫切需要开发新的治疗方法。T细胞过继免疫治疗是很有前途的MM治疗方法。Tc9是一类新型抗肿瘤效应细胞。我们前期研究发现TL1A促进Tc9生成。然而，TL1A诱导的Tc9（TL1A-Tc9）的抗肿瘤效应还不清楚。我们发现TL1A-Tc9除了表达IL-9外，也表达大量的IL-24。IL-24是IL-10家族成员，有胞内和分泌型二种形式。研究发现细胞内IL-24是抑癌基因，可直接介导肿瘤细胞凋亡。分泌型IL-24也具有抗肿瘤活性。据此，我们假设TL1A-Tc9具有强有力抗肿瘤活性，且其抗肿瘤活性依赖于IL-24。在本项研究中，我们将阐明TL1A-Tc9的生物学特性及抗肿瘤活性；阐明TL1A-Tc9的抗肿瘤作用依赖于IL-24；并以5TGM1小鼠MM为模型，阐明TL1A-Tc9对MM的治疗效果，为其临床应用提供前期数据。我们的研究具有重要的理论意义和临床应用价值。

T细胞过继免疫治疗在肿瘤治疗中发挥重要作用，Tc9细胞是一类新型具有优异抗肿瘤效果的T细胞亚群。因此优化Tc9细胞，促进Tc9细胞发挥抗肿瘤效果尤为重要。TL1A作为肿瘤坏死因子家族成员，可以调控多种Th细胞亚群的分化及功能，包括抗肿瘤效应细胞Th9细胞。而Tc9细胞与Th9细胞存在相似的特性，据此，我们假设TL1A具有促进Tc9分化并产生强效抗肿瘤作用。通过本研究，我们明确了TL1A促进Tc9细胞生成，促进Tc9细胞增殖并抑制其凋亡；阐明了TL1A通过活化NF-κB信号通路促进Tc9细胞分化；证实了TL1A促进Tc9细胞分泌颗粒霉素B和穿孔素从而发挥抗肿瘤效应。该项目阐明了TL1A对Tc9抗肿瘤细胞的作用，为T细胞免疫治疗提供新策略，具有重要的理论意义和临床应用价值。