Unraveling the genetic pathways underlying actin remodeling-mediated cancer immune evasion

Immunotherapy, in particular immune checkpoint inhibitors, is one of the most promising therapeutic modalitiesto treat cancer. However, it faces important challenges. First, cancer cells can hijack several inhibitory checkpoint pathways gaining resistance to inhibitors, which implies development of combinatorial immunotherapy strategies associated with higher toxicity. Second, tumors use other types of mechanisms to avoid elimination by the immune system. We recently discovered a process that is widely conserved across cancer types and that functions as unique point of convergence for multiple immune evasion mechanisms. This process, which we termed "actin response", consists in a quick and massive polarization of actin filamentsto the interface between tumor cells and cytotoxic lymphocytes. Remarkably, tumor cell susceptibility to lymphocyte-mediated killing can be experimentally controlled by manipulating the ability of tumor cells to mount an actin response. Thus, the actin response represents a promising and innovate point of intervention to restore an effective anti-tumor immune response in patients. Using single-cell RNA sequencing, we aim at unraveling the genetic pathways conferring tumor cells with the ability to mount an actin response and escape lymphocyte attack. The TRANSACTINg project is a crucial step toward the translation of our pioneering data on the role of actin in tumor immune evasion into clinical applications.