Plasma membrane repair protects tumor cells against killer T cell assault

Protein-mediated cell membrane repair protects cancer-derived cells against T cell attack, researchers report. The findings reveal new insights into how tumor cells escape death, which could be helpful in enhancing the efficacy of cancer immunotherapies. Cytotoxic T lymphocytes (CTLs) target and destroy virus-infected and tumor cells by secreting a pair of protein toxins, perforin and granzymes. To kill their targets, CTLs release perforin, a pore-forming toxin, which creates lesions in the target cell’s plasma membrane. Cytotoxic granzymes pass through these portals and induce target cell death. However, escaping cell death is one of the hallmarks of cancer cells and how they survive T cell attack is poorly understood. To determine how some tumor cells fight back and avoid this fate, Alex Ritter and colleagues combined high-resolution imaging data with functional analysis in live cells. They found that tumor-derived cells resist attack through endosomal sorting complexes required for transport (ESCRT) proteins, which are involved in the repair of small cellular membrane wounds. Ritter et al. show that ESCRT proteins recruited in target cells to the sites of perforin pores drive membrane repair, thereby delaying or preventing granzymes from entering and killing the cell. According to the authors, inhibiting ESCRT activity in cancer-derived cells enhanced the cells’ susceptibility to CTL killing. In a related Perspective, Norma Andrews further discusses the study and its findings.