放疗与CTLA-4抑制剂具有协同作用，可诱导远隔效应，使患者获益。如何增强远隔效应是亟待解答的临床问题。研究认为naïveT细胞活化是实现远隔效应的重要前提，但其机制尚未明确。申请人前期研究发现CD28诱导活化信号通路特征性改变，是naïveT细胞活化的关键调控因子。并且，CD28与CTLA-4高度同源，CD28信号亦受CTLA-4抑制剂调控，申请人预实验显示CTLA-4抑制剂可促进CD28介导的naïveT细胞活化。据此提出，CD28调控naïveT细胞活化在放疗联合CTLA-4抑制剂诱导远隔效应中发挥了关键作用。本研究拟利用体外模型研究CD28调控放疗诱导的naïveT细胞活化及功能，并进一步利用体内模型研究CD28信号在远隔效应中的作用及机制。本研究的创新点在于以CD28为枢纽建立了放疗和CTLA-4抑制剂诱导远隔效应机制的联系，有助于为临床增强远隔效应提供新的靶点和研究思路。

Radiotherapy has been reported a synergistic effect with CTLA-4 inhibitor to induce abscopal effect which was demonstrated clear benefit for some patients. How to enhance abscopal effect is a clinical question that needs to be answered urgently. Studies suggested that naïve T cell activation is the physiological basis for achieving abscopal effect, nevertheless the mechanism of that is not yet completely understood. We have previously reported that activation of naïve T cells is crucially dependent on CD28 induced distinctive signaling. Moreover, CD28 is a homologous to CTLA-4 thus the CD28 signaling is regulated by CTLA-4 inhibitors. Our preliminary experiments showed that CTLA-4 inhibitor further promoted CD28-mediated naïve T cell activation. Therefore we hypothesize that CD28-mediated naïve T cells activation plays a significant role in abscopal effect induced by radiotherapy combined with CTLA-4 inhibitor. This study intends to study CD28 regulated naïve T cell activation induced by radiotherapy and its function by using in vitro model, and to investigate the role and mechanisms of CD28 signal in mediating abscopal effect by using in vivo model. This study is innovative in establishing the link between radiotherapy and CTLA-4 inhibitor based on CD28 signaling, to reveal their synergistic effects to induce abscopal effect. This study may provide new insight and strategies in the clinic for optimizing radiotherapy and immunotherapy combination.