A Listeria-Derived Polypeptide Promotes In Vivo Activation of NK Cells for Antitumor Therapy

Immunotherapies have shown promise in treatment of cancer, but more potent and targeted therapies are needed. Natural killer (NK) cells are lymphocytes with innate ability to recognize and lyse tumor cells. When activated, they also produce type II interferon (IFNγ) to orchestrate the activity of other immune cells. Strategies to elicit NK cell activation in vivo have potential usefulness in anti-tumor immunotherapies. Here, we report on a strategy to stimulate NK cell activation and anti-tumor activity in mice with established B16.F10 murine melanomas. We and others previously observed that NK cells are rapidly activated during infection by pathogens such as the bacterium Listeria monocytogenes (Lm). A secreted Lm virulence protein, p60, and a fragment of p60 termed L1S were previously shown to stimulate innate immune responses and promote NK cell activation. We purified recombinant L1S and characterized its activity in cell culture studies. Recombinant L1S protein was also observed to promote accumulation and robust NK cell activation in the lungs when given via intratracheal instillation to control and tumor-bearing mice. Importantly, therapeutic administration of a single L1S dose was found to significantly reduce the number and area of "metastatic" tumor nodules on the lungs of mice with established B16.F10 murine melanomas. Depletion studies showed that these antitumor effects were dependent on NK cells and IFNγ. These data provide proof of concept that administration of a single immune-modulating microbial polypeptide can be used to therapeutically boost NK cell in vivo activation and promote anti-tumor responses.