High-content drug screening to inhibit actin cytoskeleton-mediated cancer immune evasion

Immunotherapy, in particular immune checkpoint inhibitors, is one of the most promising therapeutic modalities
to treat cancer. However, it faces important challenges. First, cancer cells can hijack several inhibitory
checkpoint pathways gaining resistance to inhibitors, which necessitates development of combinatorial
immunotherapy strategies. Second, tumours use other types of mechanisms to avoid elimination by the
immune system. We recently discovered a process, termed "actin response" that is widely conserved across
cancer types and that functions as unique point of convergence for multiple immune evasion mechanisms. The
actin response consists in a quick and massive accumulation of actin filaments, the main constituents of the
actin cytoskeleton, at the interface between tumour cells and cytotoxic lymphocytes, such as natural killer (NK)
cells and CD8+ T cells. Previous in vitro and in vivo investigations have shown that the susceptibility of tumour
cells to lymphocyte-mediated killing can be controlled by manipulating the ability of tumour cells to mount an
actin response. We propose to use the actin response as an innovative therapeutic point of intervention
restoring an effective anti-tumour immune response in patients. In the ACTIDRUG project, we plan to screen
FDA-approved drug libraries for actin response-disrupting compounds, using a high-content phenotypic drug
screening assay. Hits will be validated and further characterized in a comprehensive series of cell imaging and
functional assays. In addition, the drug effect on tumour cell susceptibility to NK and CD8+ T cell-mediated
killing will be carefully evaluated using different cancer cell models.