Figures & data
Figure 1 NK cells and other immune cells in the tumor microenvironment. NK cells of the CD56dim CD16+ phenotype secrete interferon-γ (IFN-γ), which increases the expression of MHC class I of tumor cells, enhancing the presentation of tumor antigens to T cells. Inhibitory checkpoint molecules expressed by NK cells can be blocked using specific monoclonal antibodies (ICIs). NK cells of the CD56bright CD16- phenotype recruit dendritic cells (DCs) to the tumor microenvironment (TME) and drive their maturation via chemokine ligands CCL5, XCL1 and FMS-related tyrosine kinase 3 ligand (FLT3L). DCs in turn stimulate NK and T cells via membrane-bound IL-15 (mbIL-15) and 4–1BBL secretion. Eventually, NK cells lyse tumor cells resulting in release of cancer antigens, which are then presented by DCs, to provoke specific T cell activation in relation with MHC class I molecules. The immunotherapeutic effect of NK cells includes the removal of immunosuppressive MDSCs.
Figure 2 Isolation, activation and propagation of allogeneic NK cells. Peripheral blood mononuclear cells (PBMCs) are prepared from healthy donors by leukapheresis. PBMC depletion of CD3+ T cells, prevents GvHD after infusion and further purification is achieved by positive CD56+ cell selection. These cell preparations are infused or activated with IL-2 or a mixture of IL-12, IL-15 and IL-18. Another method for NK cell stimulation involves ex vivo coculture with the K562 cell line expressing membrane-bound IL-15 (mbIL-15) and 4–1BBL that is irradiated to abolish expansion. Umbilical cord blood NK cells can be used similar to peripheral blood NK cells or enriched for CD34+ hematopoietic progenitors, followed by differentiation to NK cells. NK cells can be gained from induced pluripotent stem cells (iPSCs) via successive hematopoietic and NK cell differentiation, followed by stimulation with cells expressing mbIL-21. Before infusion of allogeneic NK cells, patients receive lymphodepleting chemotherapy to facilitate temporary engraftment of the infused NK cells.
