Role of Co-inhibitory Molecules in Tumor Escape from CTL Attack

Abstract

The immune system can be a potent defense mechanism against cancer. Especially CD8+ cytotoxic T lymphocytes (CTL) have a great killing capacity towards tumor cells. However, their potential is often dampened by immune suppressive mechanisms in the tumor microenvironment. Co-inhibitory molecules (CIM) expressed by tumor cells, immune cells and stromal cells in the tumor milieu can severely hamper CD8+ T-cell responses against cancer cells. Today, a variety of co-inhibitory molecules, including PD-1, CTLA-4, LAG3, BTLA, Tim-3 and CD200R, have been implicated in tumor escape from CTL attack. Sustained signaling via these CIM can result in functional exhaustion of T-cells, a process in which the ability to proliferate, secrete cytokines and mediate lysis of tumor cells is sequentially lost. In this chapter, we discuss the influence of co-inhibitory pathways in suppressing CD8+ T-cell function in various immune settings. These include the natural immune surveillance by CTL against tumor cells, or in therapeutic settings like allogeneic stem cell transplantation or chimeric antigen receptor (CAR) T-cell therapy. In addition, we discuss exciting pre-clinical and clinical data of immunotherapeutic approaches interfering with negative co-signaling, either as monotherapy or in conjunction with vaccination strategies. Numerous studies indicate that co-inhibitory signaling limits the clinical benefit of current CTL-based therapies. Therefore, interference with CIM is an attractive immunotherapeutic intervention for cancer therapy.