Reinvigoration of exhausted T cells

During immune responses, antigen-specific T cells are regulated by various mechanisms including inhibitory receptors and regulatory T cells to avoid excessive and persistent immune responses. These regulatory mechanisms, called ‘immune checkpoint’, suppress T cell responses particularly in chronic viral infection and cancer, in which viral antigens or tumor antigens persist for a longtime, and lead to T cell exhaustion in patients with chronic viral infection or cancer. Among them, programmed cell death 1 (PD-1) are the most well-known receptors and have been targeted for drug development. As a result, anti-PD-1 (or anti-PD-L1) blocking antibodies were developed for cancer treatment and known as ‘immune checkpoint inhibitors’. However, anti-PD-1 (or anti-PD-L1) blocking antibodies fail to control tumors in a significant proportion of cancer patients. Therefore, it is an important question how the coverage of immune checkpoint inhibitors can be extended to the majority of cancer patients. Currently, we are studying strategies to improve treatment responses of anti-PD-1, including novel target molecules and biomarkers predicting treatment responses.