Inhibitory receptors as targets for cancer immunotherapy

Inhibitory receptors expressed on T cells control immune responses while limiting autoimmunity. However, tumors can hijack these "checkpoints" for protection from immune attack. Tumor-specific T cells that exhibit an exhausted, unresponsive phenotype express high levels of inhibitory receptors including CTLA4, PD1, and LAG3, among others. Intratumoral regulatory T cells promote immunosuppression and also express multiple inhibitory receptors. Overcoming this inhibitory receptor-mediated immune tolerance has thus been a major focus of recent cancer immunotherapeutic developments. Here, we review how boosting the host's immune system by blocking inhibitory receptor signaling with antagonistic mAbs restores the capacity of T cells to drive durable antitumor immune responses. Clinical trials targeting the CTLA4 and PD1 pathways have shown durable effects in multiple tumor types. Many combinatorial therapies are currently being investigated with encouraging results that highlight enhanced antitumor immunogenicity and improved patient survival. Finally, we will discuss the ongoing identification and dissection of novel T-cell inhibitory receptor pathways, which could lead to the development of new combinatorial therapeutic approaches.