Cytotoxic T lymphocytes (CTL) play a key role in the immune response against tumor cells via the rapid secretion of lytic molecules such as perforin and granzymes within a specialized secretory area named lytic synapse. Perforin-mediated pore formation allows granzymes to entry into target cells, triggering the apoptotic process. Because of their remarkable ability to kill, CTL are at the heart of therapeutic strategies aiming at improving anti-tumor immune response.
Our hypothesis is that the limited efficacy of CTL in their fight against tumors is the result of an unfavorable balance between CTL ability to kill tumors and intrinsic tumor resistance to CTL cytolytic activity. In a recent study, we described a novel mechanism of melanoma cell defense from CTL attack that is based on the rapid secretion of their lysosomes/late endosomes at the lytic synapse leading to perforin degradation.
To better understand such synaptic defense we are investigating the mechanisms that trigger and regulate melanoma cell secretory response and the time-kinetics of this response. Our results show that: i) lysosome secretory burst is triggered in melanoma cells by their plasma membrane perforation at the lytic synapse; ii) both pre-treatment of melanoma cells with cell permeable calcium chelators and silencing the Ca2+ sensor synaptotagmin VII reduce melanoma cell capacity to resist to CTL attack; iii) Ca2+-gradients are formed in melanoma cells at the site of perforin binding; iv) a rapid Ca2+-dependent reparative membrane turnover is triggered in melanoma cells early after CTL attack.
Our results indicate that melanoma cells have hijacked a Ca2+-dependent membrane repair mechanisms to rapidly secrete their lysosomes into the synaptic cleft and, in turn, resist to CTL attack. In perspective, a better definition of such synaptic defense can pave the road to novel therapeutic strategies aiming at potentiating the efficacy of CTL responses in melanoma patients.