Role of CD28 costimulation in T cell receptor gene therapy of cancer

近年来，操纵免疫系统抗击癌症的努力取得了成效，使用针对PD1(L1)的检查点抑制剂的治疗方法取得了进展，在过继T细胞疗法(ATT)中涉及将癌症靶向T细胞转移到患者身上。PD1在肿瘤浸润性T淋巴细胞(TIL)上表达上调，而PD-L1在许多肿瘤上表达上调。阻断PD1信号有助于TIL通过恢复其增殖和效应功能来克服免疫抑制的肿瘤微环境。主要机制包括通过CD28共刺激受体重新激活信号，否则该受体会被PD1信号沉默。TIL抗癌的能力也在另一种方法中得到利用，包括分离和体外扩增，随后是ATT。ATT的潜力已经扩展到基因修饰的T细胞，通过引入T细胞受体(TCR)或嵌合抗原受体(CARS)，它们对肿瘤抗原(AGS)的特异性已经改变。CD19-CAR靶向治疗B细胞恶性肿瘤已经取得了最大的成功，然而，CAR和TCR修饰的T细胞对实体瘤的有效性尚未显示出来。ATT的动物肿瘤模型已经证明，如果T细胞表现出强大的效应功能，肿瘤复发是可以避免的。这种有效的反应与肿瘤间质抗原提呈细胞(APC)上交叉表达的AGS的识别有关。由于在检查点抑制剂治疗过程中，CD28信号在打破TIL的耐受性方面起着重要作用，因此肿瘤间质APC的抗原交叉压抑的主要作用可能是提供CD28共刺激，以增加T细胞效应功能。我们公布的和初步的数据表明，情况就是这样。这个项目的总体目标将是回答这个问题，并将这一知识应用于翻译使用。具体目的将是阐明ATT过程中抗原交叉压低和CD28共刺激之间的联系，并通过体内可诱导的CD28共刺激来提高T细胞的抗肿瘤活性。这些发现将完善目前关于ATT中肿瘤抗原交叉压低作用的概念，并将利用它们进入一种新的治疗方法，具有更广泛的临床影响的潜力。

Efforts to manipulate the immune system to fight cancer have been paying off in recent years with advances achieved in therapies using checkpoint inhibitors targeting PD1(L1), and in adoptive T cell therapies (ATT) involving transfer of cancer-targeting T cells to the patients. PD1 expression is often upregulated on tumor infiltrating T lymphocytes (TILs), while the PD-L1 expression is upregulated on many tumors. Blocking the PD1 signaling helps TILs to overcome the immunosuppressive tumor microenvironment by restoring their proliferation and effector function. The main mechanism involves reactivation of signaling through the CD28 costimulatory receptor, which is otherwise silenced by PD1 signaling. The ability of TILs to fight cancers has also been exploited in an alternative approach involving their isolation and ex vivo expansion, followed by ATT. The potential of ATT has been extended to gene-modified T cells, where their specificity has been altered towards tumor antigens (Ags), either by introducing T cell receptors (TCRs) or chimeric antigen receptors (CARs). The biggest success has been achieved with CD19-CAR-targeted therapy of B cell malignancies, however, the effectiveness of CAR- and TCR-modified T cells against solid tumors is yet to be shown. Animal tumor models of ATT have shown that tumor recurrence can be avoided if T cells display robust effector function. Such potent response is associated with recognition of crosspresented Ags on tumor stroma antigen presenting cells (APCs). Since CD28 signaling plays an important role in breaking tolerance of TILs during checkpoint inhibitor therapy, it’s possible that the main role of Ag crosspresentation by the tumor stroma APCs is to provide CD28 costimulation to increase T cell effector function. Our published and preliminary data indicate that this is the case. The general goal of this project will be to answer this question and to apply that knowledge to translational use. The concrete objective will be to elucidate the link between Ag crosspresentation and CD28 costimulation during ATT, and to improve T cell anti-tumor activity by inducible in vivo CD28 costimulation. These findings will perfect the current concepts regarding the role of tumor Ag crosspresentation during ATT, and will harness them into a new therapeutic approach that has the potential for broader clinical impact.