Natural killer cells in pancreatic cancer stroma

Figure 4 Cytotoxic granule convergence and microtubule organising centre polarisation. A: Following receptor stimulation leading to natural killer (NK) cell activation, leukocyte function-associated antigen 1 engages with its ligand ICAM1 on the malignant cell, forming a stable immunological synapse; B: F-actin accumulates and polymerises at the immune synapse, forming a filamentous mesh which modulates the release of cytolytic granules. Tubulin microtubules then form from the microtubule organising centre (MTOC); C and D: Cytotoxic granules converge on the microtubules (C) and are polarised towards the MTOC where they converge (D); E: This granule movement is dependent on dynein/dynactin motor function. Dynamic rearrangement of the microtubules facilitates polarisation of MTOC towards the immunological synapse; F and G: This polarisation is stimulated via Integrin-linked kinase, paxillin, Pyk2 and RhoGEF7 signalling. Following polarisation to the immunological synapse, a subsection of cytotoxic granules fuse with the plasma membrane (F) (a process largely regulated by Munc 13-4 and Rab27a) and undergo degranulation via either complete or incomplete fusion (G); H: Cytotoxic granules which do not degranulate are recycled and are hypothesised to remain converged at the MTOC to facilitate serial NK cell killing. Granules which undergo incomplete fusion are rapidly recycled through clathrin mediated endocytosis of granule membrane proteins, further facilitating serial killing; I: Finally, the malignant cell undergoes perforin induced necrosis or granule dependent apoptosis. NK cells detach from the malignant cell and move on to the next target.