同种异体树突状细胞激活的KLRG1+CD8 T细胞抗肿瘤机制研究

Immune inhibitory microenvironment induced by tumorigenesis comprises the barrier for antitumor immunity. So the key step is to break through the inhibition to immune cells. Allogeneic stimulation is an effective approach for activation of immune system, which was also proved by the observation of graft-versus-tumor in bone marrow transplantation. However, the study on antitumor responses by allogeneic stimulation is still not systemic, and the mechanisms involved are also unclear. Based on our established model that allogeneic dendritic cells could activate antitumor responses, we want to figure it out systemically, and explore the detailed mechanisms. We have found in our previous work that a population of KLRG1+CD8 T cells increased dramatically after allogeneic DC-stimulation. Then antibody depletion and adoptive transfer further proved that these cells were involved in allogeneic DC-activated antitumor responses. Therefore, we will focus our mind on the immunological features and antitumor-related function of KLRG1+CD8 T cells, by which a new antitumor therapeutic strategy could be mentioned.

肿瘤发生所形成的免疫抑制性微环境是免疫系统行使抗肿瘤功能的障碍。因此，解除肿瘤微环境对免疫细胞的抑制，成为肿瘤免疫治疗的关键。同种异体刺激是免疫活化的有效手段。骨髓移植中移植物抗肿瘤（GvL）现象已经证明同种异体细胞激发抗肿瘤反应的能力。但目前对同种异体免疫反应抗肿瘤的研究尚不系统，相关机制并不明确。本课题以同种异体DC免疫激发抗肿瘤效应动物模型为基础，探索同种异体DC免疫激发的抗肿瘤作用及其机制。前期工作发现，KLRG1+CD8 T细胞在同种异体DC免疫后显著增多，抗体清除和过继回输实验均证明该亚群参与了同种异体反应激发的抗肿瘤效应。因此本课题将以KLRG1+CD8 T细胞为中心，深入研究该亚群的免疫学特征和抗肿瘤相关功能特性；并试图借此探索以KLRG1+CD8 T细胞为主体的肿瘤治疗新方法。

肿瘤发生所形成的免疫抑制性微环境是免疫系统行使抗肿瘤功能的障碍。因此，解除肿瘤微环境对免疫细胞的抑制，成为肿瘤免疫治疗的关键。同种异体刺激是免疫活化的有效手段。骨髓移植中移植物抗肿瘤（GvL）现象已经证明同种异体细胞激发抗肿瘤反应的能力。但目前对同种异体免疫反应抗肿瘤的研究尚不系统，相关机制并不明确。骨髓移植中移植物抗肿瘤（GvL）现象已经证明同种异体细胞激发抗肿瘤反应的能力。我们用不同种类的免疫细胞免疫受体B6小鼠,发现能够激发强烈的抗肿瘤免疫保护能力，从而抑制多种肿瘤的生长。对受体小鼠的淋巴细胞进行了分析，结果显示, 免疫后CD8 T细胞显著增加,并表达KLRG1效应记忆T细胞标志。体内过继回输及体外共培养实验表明，这群KLRG1 + CD8 T细胞可以有效杀伤肿瘤细胞，其杀伤机制有赖于Granzyme B -和Fas / FasL-途径，其杀伤效应没有肿瘤抗原特异性和且这类细胞能通过高表达乙酰肝素酶而迁移和浸润到肿瘤细胞中。将这群细胞过继回输可以有效抑制肿瘤。同种异体DC细胞也可以有效清除小鼠体内的肿瘤残余，并且结合抗PD1抗体联合治疗可以提高抗肿瘤效应。我们的研究表明,同种异体DC 免疫通过激发受体KLRG1 + CD8 T细胞迅速扩增，从而诱导有效的抗肿瘤效应，可据此将同种异体DC研发作为预防和治疗肿瘤疫苗。