Dynamic Behaviors and Strategies of Natural Killer Cell Chemotaxis towards Distinct Cancer Targets

Cell motility plays a crucial role in diverse physiological and pathological processes. Most biophysical and statistical studies of cell motility examine the migration of bacteria and epithelial cells, and we know much less about the quantitative principles underlying immune cell motion. In this proposed project, we aim to elucidate the dynamic control over the chemotactic motion of an important immune cell type, Natural Killer (NK) cells. NK cells are cytotoxic lymphocytes that detect and eliminate virus-infected cells and cancer cells. The strong cytotoxicity of NK cells against cancer targets render NK cells promising therapeutic candidate for cancer treatment. However, despite data showing directed NK cell migration towards the cancer targets is the rate-limiting step of NK- tumor cell interaction in vivo, our quantitative and mechanistic understanding of this critical motility process is very limited.

We have previously developed single-cell microscopy assays to measure the real-time dynamics of NK-cancer cell interactions, and employed machine learning-assisted single cell tracking to quantify the target-directed NK cell motion. We found NK cell polarization played an important role in regulating its migration and such polarization- modulated motility varied significantly in response to different target cell types, likely due to variable target secretion of chemotactic cytokines/chemokines. Building on these novel observations, in this project we will expand the measurements to obtain large NK cell motility datasets under a variety of NK-target cell interaction conditions, and then construct a mathematical model for NK cell chemotaxis based on the in-house experimental data. Computational analysis will be performed to explore the model behaviors, in particular the NK cell response to environmental cues in relation to their nonrandom motility. The key and previously unresolved questions that our study will address include: (1) how the polarization-modulated NK cell chemotactic motion quantitatively depends on the target cells, particularly via the differential cytokine/chemokine microenvironment; (2) how chemotaxis depends on NK cell population density (i.e., collective group behavior); and (3) what quantitative features of the chemotactic signaling can be inferred from the differential NK cell migration dynamics.

Overall, the wealth of data generated through targeted experiments in this project will enable us to propose and quantitatively evaluate the critical search strategies employed by NK cells to detect and migrate towards abnormal cell targets. The integrated approach that we adopt is highly novel and will also serve as a protocol for elucidating the chemotactic dynamics of other important immune cell types, e.g., T cells.