Figure 1.

NK cell-based approaches in the immunotherapy of tumors and leukemias. (A) NK cell function may be greatly hampered by inhibitory factors and/or cytokines produced by tumor cells or cells of the tumor microenvironment (e.g., fibroblasts, F) and by hypoxia that primarily induce down-regulation of activating NK receptors. (B) CD16-mediated antibody dependent cytotoxicity (ADCC) appears to be poorly susceptible to the inhibitory tumor microenvironment. This mechanism may contribute to the positive clinical outcome of patients treated with tumor-specific monoclonal antibodies (mAbs). (C) In the T-depleted haplo-HSCT, KIR⁺ alloreactive NK cells derived from donor HSC (generated after 6–8 weeks) kill leukemia blasts (inducing GvL), DC (preventing GvHD), and T cells (preventing graft rejection) remaining after the conditioning regimen. (D) In haplo-HSCT, early leukemia relapses and severe viral infection may occur during the time interval (6–8 weeks) required for the generation of efficient alloreactive NK cells. The novel approach based on TCR α/β⁺- and B cell-depletion allows the infusion of donor-derived mature alloreactive NK cells and TCR γ/δ⁺ cells together with HSC, thus allowing a better control of leukemia relapses, GvHD, graft rejection, and viral infection/reactivation.