Killer immune cell swarming and solid tumor interactions

Cytotoxic lymphocytes, also known as killer immune cells, can migrate rapidly and with striking versatility in a continuous search for cells to subdue. Adoptive cell transfer immunotherapies attempt to harness the capacity of T cells and natural killer (NK) cells to effectively locate, engage and kill cancer targets, yet they have thus far largely proved unsuccessful when targeting solid malignancies due to insufficient tumor infitration. The mechanisms and cellular forces that underpin the coordinated movements and interactions of killer immune cells and tumor cells are incompletely understood.

We investigate the intercellular signaling and mechanical forces that these killer immune cells employ to effectively infiltrate and attack solid tumors. Using an integrative and multidisciplinary method encompassing advanced live-cell microscopy, image analysis, biophysics and modelling, we are uncovering the intricate mechanobiology of T and NK cell-mediated tumor rejection. We reveal independent emergent behaviour in killer immune populations attacking tumor masses. Killer lymphocytes coordinate their migration in a process reminiscent of the swarming observed in insects and neutrophils. Killer cells engaging tumor targets accelerate the recruitment of distant immune cells through long-range signalling, mediated via the secretion and diffusion of chemoattractant factors. Immune cells newly arriving at the tumor augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. We are further exploring the influence of stromal cells that surround the tumor core and contract and remodel the extracellular matrix, rendering the tumor microenvironment impassable to the killer immune cells. Overall, our ex vivo models with tumor spheroids embedded in collagen matrices containing immune and stromal cells allow us to study the mechanisms and signaling axes that drive the rapid convergence of killer cells around solid tumors, and their exclusion from the core.