Title: Prospects for off-the-shelf NK cell therapy
Abstract: Discrimination of self from non-self through the continuous selection of effector specificity is the backbone of effective immunity. For natural killer (NK) cells this specificity is achieved by unique combinations of variable germ-line receptors that recognize self-MHC antigens. Inhibitory interaction between NK cell receptors and self-ligands is the key determinant in functional potentiation of pre-primed effector responses, a process termed NK cell education. The calibration of effector potential to self-MHC allows for the rapid sensing of discontinuity in the level of MHC expression during infection, cellular stress or tumor transformation, whilst operating within a framework of overall tolerance to normal tissues.
In this talk, I will discuss new insights into the underlying mechanisms behind the functional diversification of human NK cells, including the dynamic imprints caused by “adaptive” NK cell responses to cytomegalovirus infection. In terms of clinical translation, new strategies to selectively expand such adaptive NK cells for off-the shelf NK cell therapy will be discussed. I will also touch upon the prospects for harnessing induced pluripotent stem cell (iPSC)-derived natural killer (iPSC-NK) cells in cancer therapy. iPSCs can be routinely generated from a variety of easily obtainable sources such as skin and peripheral blood and are able to undergo essentially unlimited expansion in vitro without losing pluripotency. Therefore, iPSCs can serve as a resource to produce unlimited numbers of NK cells for cell therapy. Moreover, iPSC-NK cells can be used as a platform for genetic engineering to improve specificity, persistence, tumor cell homing and functionality of the final cell product. These functional edits are superimposed on the innate reactivity of NK cells to stress ligands and MHC downregulation.