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

点击翻译按钮获取中文摘要

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.