PD-L1/PD-1通路在树突状细胞提呈次优势抗原免疫应答中的调控机制

PD-L1 (also named B7-H1) is an important target of cancer therapy. PD-L1 down-regulates the immune responses by binding to PD-1 on T cells. PD-L1 is also reported to act as a receptor on tumor cells, receive single from PD-1 and rend tumor cells resistance against CTL-mediated lysis. PD-L1 on DCs also has an important role in regulating DC-T interaction. PD-L1 blockade could enhance the antigen presenting capacity of DC, and thus increase the proliferation of antigen specific T cells. However, there are thousands of antigens produced when tumor happens, and DC would presents more than one antigens at a time. These different antigen peptides could not stimulate T cell response equally and form a repeatable immunodominance hierarchy according to the number and activity of T cells they stimulated. Whether PD-L1 on DC could regulate dominant and subdominant antigens equally? Whether PD-L1 could also serve as a receptor on DCs? To address these, we propose to select antigens of different dominant hierarchy to determine the regulatory effect of PD-L1/PD-1 on antigen-specific T cell responses when they was presented on DCs simultaneously, and then further explore the role of PD-L1 on DCs’ differentiation, antigens presentation, especially those of different dominant hierarchy. This study can provide a theoretical support for the further understanding of tumor escape and application of PD-L1/PD-1 antibody to the clinical treatment of cancer.

PD-L1(又称B7-H1)是重要的癌症免疫治疗靶点。PD-L1通过与T细胞表达的受体PD-1结合负调控免疫应答。 PD-L1也可作为受体，向肿瘤细胞传递信号使其抵抗CTL的清除。PD-L1在树突状细胞（DC）激活T细胞的过程中也发挥重要作用。阻断PD-L1后，DC抗原提呈能力增强，抗原特异性T细胞增殖水平提高。肿瘤发生时产生大量抗原，DC会同时提呈多种抗原并根据激活T细胞的强度形成免疫优势等级。PD-L1阻断是否同等地增强DC对优势与次优势抗原的提呈？且DC表达的PD-L1是否也会向其传递逆向信号？为回答以上问题，本项目拟选取不同优势等级的抗原，确定DC表达的PD-L1对不同抗原特异性T细胞应答的调节作用，然后探讨PD-L1对DC的成熟分化，以及抗原提呈能力有何影响。该研究可为进一步阐明肿瘤逃逸机制做出努力，同时也为PD-L1/PD-1抗体药更广泛地应用于癌症临床治疗提供理论支持。

肿瘤免疫微环境中B7-H1上调表达，与PD-1结合抑制免疫反应，介导肿瘤发生逃逸，即产生获得性抵抗。B7-H1/PD-1的阻断性抗体可以克服这种抵抗，使肿瘤消退，因而被广泛应用于肿瘤的临床治疗。除肿瘤细胞外，B7-H1也可在树突状细胞DC（Dendritic Cell）上表达，促进DC的抗原提呈能力，在DC激活T细胞过程中起着关键的调控作用。肿瘤发生时，在体内产生成大量抗原，DC 细胞可同时提呈多种抗原并形成免疫优势等级。然而目前的研究主要集中于T细胞对单一抗原的整体反应，因此B7-H1是否能同等调节各个不同优势等级的抗原特异性T 细胞的激活，进而产生广谱T 细胞应答还有待进一步研究。..本研究表明DC在同时提呈多个不同免疫优势等级的抗原时，B7-H1/PD-1通路的阻断能够增强优势CTL（Cytotoxic T Lymphocyte）细胞活性，但同时抑制了次优势CTL细胞，使带有次优势抗原的肿瘤细胞发生逃逸，得以生长。我们推测产生这一“双向调节”的可能机制是B7-H1缺失使DC易于被优势的CTL杀伤，从而缩短了DC上次优势抗原的提呈时间，而使次优势T细胞活化减少。因此，DC细胞表达的B7-H1有利于维持T细胞应答的克隆多样性。本研究阐述了B7-H1/PD-1抗体治疗肿瘤无反应或治疗后复发的一种机制，即B7-H1的阻断增强了肿瘤免疫中优势抗原的应答，使免疫系统集中攻击带有优势抗原的肿瘤细胞，但同时阻断抗体对次优势抗原的应答的抑制，使带有次优势抗原的肿瘤细胞有足够的时间发生基因突变，逃避免疫应答，维持肿瘤的生长或导致复发。此外，本研究所提出的理论解决了肿瘤DC疫苗研究领域中需要关注的一个重要问题：在B7-H1阻断的情况下，DC疫苗应该对不同抗原分别进行包被，避免次优势T细胞被干扰，从而产生种类多样且增强的T细胞反应，有效抵御肿瘤发生逃逸。本研究为临床上PD-1阻断抗体与DC疫苗的有效联用提供理论支持。