In vitro T lymphopoiesis: IPSCs for T cell generation, foundations, innovations, and future directions

T cells are a fundamental component of the human adaptive immune system possessing critical functions ranging from recognition of foreign antigens to the generation and maintenance of immunologic memory for immune surveillance. These properties can be harnessed and further manipulated ex vivo to derive autologous cellular agents for the treatment of cancer. Recent expansion in the understanding of how the earliest pluripotent stem cells differentiate naturally into T cells coupled with advances in genetic engineering has opened doors for their therapeutic potential. Moreover, human pluripotent stem cells can be selectively directed toward hematopoiesis and both these in vitro-derived early hematopoietic progenitors and isolated hematopoietic stem progenitors can then be subjected to T specification conditions as a means of deriving T cells. This involves the utilization of various coculture systems, which employ Notch ligand expressed by stromal cells tantamount to normal T-cell development within the thymus. In this chapter, we will discuss the history of in vitro T-cell lymphopoiesis as well as the current methods being used to streamline T lineage commitment and T-cell generation from multiple stem cell sources. We will also review how gene editing techniques have revolutionized T-cell-based therapies and explore how the combination of in vitro T-cell generation and genetic enhancement of these cells has the potential to transform the efficacy and availability of cancer-directed T-cell immunotherapy.