OVERCOMING TUMOR IMMUNE EVASION BY TARGETING THE ACTIN RESPONSE

Natural killer (NK) cells are sentinels of the innate immune system able to recognize and eradicate diseased cells, including cancer cells. AlthoughNK cells act as a first line of defenseagainst tumor development and metastasis, some tumorcells acquire the capacity to evade immunesurveillance, leading to cancer progression. Recently,weuncoveredapivotal role forthe actin cytoskeleton in mediatingbreast cancer cell resistance to NK cell-inducedcell death.Our findings show that, upon NK cell attack,amassive accumulation of actinnear the cell-cell contactsite rapidlytakes place in resistant target cells. Thisso-called "actin response" protects NK cell-conjugated target cells from apoptosis by decreasing intracellular levels of the cytotoxic protease Granzyme B. In additionto this mode of action,there are indications that the actin response could also actas a physical barrierinhibitingthe formationoftight conjugatesbetween NK cells and their targets. The ACTIMMUNE project aims at evaluating this possibility anddissecting the early steps of the actin response using state-of-the-art live cell imaging approaches. In addition, it aims at validating the role of the actin response in tumor immune evasion in a relevant mouse model and at providing a rationale for targeting this process as a therapeutic approach to improve the antitumor immune response. Finally, the ACTIMMUNE project aims at identifying clinically-relevant targets to interfere with the actin response in patients.