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

近年来，操纵免疫系统对抗癌症的努力已经取得了成效，在使用靶向PD 1（L1）的检查点抑制剂的治疗中取得了进展，并且在过继性T细胞治疗（ATT）中涉及向患者转移癌症靶向T细胞。PD 1表达通常在肿瘤浸润性T淋巴细胞（TIL）上上调，而PD-L1表达在许多肿瘤上上调。阻断PD 1信号传导有助于TIL通过恢复其增殖和效应子功能来克服免疫抑制性肿瘤微环境。其主要机制涉及通过CD 28共刺激受体重新激活信号传导，否则其会被PD 1信号传导沉默。TILs对抗癌症的能力也已在另一种方法中得到利用，包括其分离和离体扩增，然后是ATT。ATT的潜力已经扩展到基因修饰的T细胞，其中通过引入T细胞受体（TCR）或嵌合抗原受体（CAR），它们对肿瘤抗原（Ag）的特异性已经改变。B细胞恶性肿瘤的CD 19-CAR靶向治疗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。ATT的动物肿瘤模型已经表明，如果T细胞显示出强大的效应子功能，则可以避免肿瘤复发。这种有效的应答与肿瘤基质抗原呈递细胞（APC）上交叉呈递的Ag的识别相关。由于CD 28信号传导在检查点抑制剂治疗期间破坏TIL耐受性中起重要作用，因此肿瘤基质APC的Ag交叉表达的主要作用可能是提供CD 28共刺激以增加T细胞效应功能。我们公布的数据和初步数据表明情况确实如此。这个项目的总体目标是回答这个问题，并将这些知识应用于翻译。具体的目标是阐明ATT过程中Ag交叉表达和CD 28共刺激之间的联系，并通过体内诱导的CD 28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肿瘤Ag交叉表达在ATT中的作用的概念，并将其用于具有更广泛临床影响潜力的新治疗方法。

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.