Actin cytoskeleton remodeling drives breast cancer cell escape from natural killer-mediated cytotoxicity

Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic NK cells. A significant fraction of breast cancer cells responded to NK cell attack via a surprisingly rapid and massive accumulation of F-actin near the immunological synapse, a process we termed 'actin response'. Live cell imaging provided direct evidence that the actin response is associated with tumor cell resistance to NK cell-mediated cell death. High-throughput imaging flow cytometry analyses showed that breast cancer cell lines highly resistant to NK cells were significantly enriched in actin response-competent cells as compared to susceptible cell lines. The actin response was not associated with a defect in NK cell activation but correlated with reduced intracellular levels of the cytotoxic protease Granzyme B and a lower rate of apoptosis in target cells. Inhibition of the actin response by knocking down CDC42 or N-WASP led to a significant increase in Granzyme B levels in target cells and was sufficient to convert resistant breast cancer cell lines into a highly susceptible phenotype. The actin response and its protective effects were fully recapitulated using donor-derived primary NK cells as effector cells. Together these findings establish the pivotal role of actin remodeling in breast cancer cell resistance to NK cell-mediated killing.

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