THE BIOLOGY BEHIND PD-1 CHECKPOINT BLOCKADE.

Programmed death 1 (PD-1) pathway inhibitors have transformed cancer therapy, leading to durable responses in some patients. However, many patients do not benefit from PD-1 blockade therapy, which highlights the critical need to identify new therapeutic targets to complement PD-1 pathway inhibitors. To address this need, we have developed an <i>in vivo</i> clustered regularly interspaced short palindromic repeats (CRISPR)-based screening platform to discover novel regulators of anti-tumor immunity. In this article, I will first discuss the biology of the PD-1 pathway and its role in regulating anti-tumor immunity. Next, I will introduce our innovative CRISPR-based platforms designed for conducting gene screens in mature immune cell lineages and for enabling gene perturbation without stimulating or manipulating immune cells, two approaches that can affect immune cell development and function. In addition, I will illustrate how these platforms facilitate discovery of new targets that can promote anti-tumor immunity and their potential to lead to more effective cancer therapies.