Efficient homing of natural killer
Efficient homing of natural killer (NK) cells in the tumor microenvironment (TME) is essential for NK mediated anti-tumor effector function. Interestingly, the NK cell population identified in the TME is dominated by non-cytotoxic cytokine producing NK cells (defined as CD56bright) cells) rather than cytotoxic NK cells. We hypothesize the lack of cytotoxic NK cells to be a major factor contributing to tumor immune evasion, and enhancing cytotoxic NK cells infiltration into the TME will inhibit tumor growth. We developed a novel 3-D collagen assay to investigate the mechanistic basis for NK cell exclusion from tumors. Using biochemical fractionation of tumor supernatants and mass spec analysis, we identified a small complement factor as the common and critical mediator of NK cell exclusion in a number of different tumors types. In collaboration with Dr. Niki Sibson, we will test the hypothesis that this small complement factor promotes NK cell exclusion from tumors through the integrin molecule LFA-1 using both genetic ablation with Crispr-Cas9 as well as specific LFA-1 conformational antibodies. In addition, this project will exploit yeast surface display technology to develop a high affinity inhibitor for the small complement factor to translate preclinical findings in mouse models to the clinic.