Studies on reinvigorating exhausted CD8 T cells in tumor by NKT cell activation

Abstract

Cancer immunotherapy using immune checkpoint inhibitors has emerged as one of the most effective treatments for cancer patients. PD-1 blockade, in particular, is a successful example of immune checkpoint blockades that provides long-term durable therapeutic effects in cancer patients with a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances anti-tumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of cancer patients to anti-PD-1 therapy remains low, providing an urgent need for the optimization of anti-PD-1 therapy for improved cure of cancer patients.<br/> In this study, I established an anti-PD-1-resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 was associated with gradual increases in CD8 T cell exhaustion. I also showed that invariant natural killer T (iNKT) cell stimulation by its synthetic ligand, α-galactosylceramide (αGC), could enhance the anti-tumor effect in anti-PD-1-resistant tumor models by restoring the effector function of tumor antigen-specific exhausted CD8 T cells. Among the cytokines produced by αGC stimulation, IL-2 and IL-12 appeared to be crucial for reinvigorating exhausted CD8 T cells in tumor-bearing mice and cancer patients. Furthermore, combining αGC-loaded antigen-presenting cells and PD-1 blockade elicits the improved antitumor activities in therapeutic murine tumor models. Thus, this study suggests that NKT cell stimulation would be a promising therapeutic candidate for the treatment of anti-PD-1-resistant cancer in humans.