The surfaces of immune cells and cancer cells are densely decorated with proteins, glycoproteins, and glycolipids that form a dynamic molecular landscape known as the glycocalyx. This crowded environment can sterically hinder close contact between immune cells and target cells, modulating key effector functions like macrophage phagocytosis and T cell killing. To explore the role of the glycocalyx in these interactions, we developed a set of quantitative tools to measure cell surface crowding and the physical properties of surface glycoproteins. We found that macrophage phagocytosis is suppressed by increased surface crowding and that different target cells exhibit distinct crowding levels, which can alter antibody binding. Using a genome-scale CRISPR interference screen, we identified mechanisms by which cells can actively tune the steric hindrance of their glycocalyx and showed that this process can be developmentally regulated. Overall, cell surface crowding is emerging as a fundamental biophysical barrier in immune interactions, suggesting that targeting crowding could provide novel strategies for enhancing cancer immunotherapy.
Daniel A. Fletcher (Sun,) studied this question.