The (re)discovery of tumor-intrinsic determinants of immune sensitivity by functional genetic screens

Abstract

Functional genetic screens by CRISPR-Cas9 allow for the unbiased discovery of proteins causally involved in complex biological processes. In recent years, this approach has been used by multiple laboratories to uncover a range of tumor cell regulators determining immune sensitivity. In this review, we provide an overview of genetic screens carried out both in vitro and in vivo. By comparative analysis we highlight commonly identified proteins and pathways that are key in establishing tumor-intrinsic immune susceptibility. Together, these screens demonstrated the importance of the antigen presentation, interferon-γ, tumor necrosis factor and autophagy pathways in governing sensitivity of tumor cells to immune attack. Moreover, they underline the complex interplay between tumor cells and their microenvironment, providing both fundamental and clinically relevant insights into the mechanisms of tumor immune resistance.

Keywords

• immunotherapy
• immune checkpoint blockade
• CRISPR-Cas9
• genetic screen
• therapy resistance