Immunotherapy has come a long way since its discovery, leading to successful outcomes such as immune checkpoint blockade and CAR-T cell therapy. However, because immunotherapy is only suitable for cancers with a specific tumour microenvironment, only a small subset of patients benefit from this treatment. More importantly, tumour cells can manipulate and evade the immune system, rendering some forms of immune therapy ineffective. While the mechanisms behind tumour immune evasion have been well-studied, most research focuses on transcriptomic and genetic factors, with limited attention given to post-translational mechanisms and intracellular trafficking of immune-regulatory components.
Autophagy, a key mechanism of cellular homeostasis, is regulated by specific genes and proteins that, when disrupted, have been shown to promote tumourigenesis and immune escape. In addition, genes involved in endocytic trafficking and apoptosis pathways also influence the tumour cell’s ability to avoid immune destruction.
In this study, we will use both a candidate-driven and CRISPR/Cas9 screen-based approach to identify key regulators within the autophagy, endocytic trafficking and apoptosis pathways that enable tumour immune evasion. Our candidate approach focuses on a central autophagy regulator, where we have discovered that its deletion confers resistance to immune-mediated killing. The mechanisms underlying this phenotype are currently under investigation.
Complementing this, a CRISPR/Cas9 knockout screen will target a broader set of genes (1,300) across these pathways. Edited cancer cells will be exposed to immune cell pressure, and gene expression analysis will identify novel regulators that contribute to immune evasion.
Together, these approaches aim to uncover molecular targets that restore anti-tumour immunity and inform future therapeutic strategies to overcome immune resistance in solid cancers.