Abstract
Treatment of hematological malignant disorders has been improved over the last years, but high relapse rate mainly attributable to the presence of minimal residual disease still persists. Therefore, it is of great interest to explore novel therapeutic strategies to obtain long-term remission. Immune effector cells, and especially natural killer (NK) cells, play a crucial role in the control of hematological malignancies. In this regard, the efficiency of allogeneic stem cell transplantation clearly depends on the immune-mediated graft versus leukemia effect without the risk of inducing graft versus host disease. Alloreactive donor NK cells generated following hematopoietic stem cell transplantation ameliorate the outcome of leukemia patients; in addition, in vivo transfer of in vitro expanded NK cells represents a crucial tool for leukemia treatment. To improve NK cell effector functions against resistant leukemia cells, novel immunotherapeutic strategies are oriented to the identification, isolation, expansion, and administration of particular NK cell subsets endowed with multifunctional anti-tumor potential and tropism toward tumor sites. Moreover, the relationship between the emergence and persistence of distinct NK cell subsets during post-graft reconstitution and the maintenance of a remission state is still rather unclear.
Highlights
Natural killer (NK) cells belong to innate lymphocytes that play an important role in the early phase of immune defense against microbial infections, and tumor growth and dissemination
Our findings suggest that CD56lowCD16low NK cells represent an intermediate state between CD56high and CD56lowCD16high NK cells
The NK cell therapeutic potential was clearly demonstrated when a potent anti-leukemic effect was observed in patients with acute myeloid leukemia (AML) undergoing mismatched/ haploidentical hematopoietic stem cell transplantation (HSCT). This protocol of transplantation relied on the generation of alloreactive NK cells with a killer cell immunoglobulin-like receptor (KIR) repertoire unable to bind to host MHC class I molecules, and was associated with a 65% probability of disease-free survival, decreased incidence of relapse, and no increased incidence of graft versus host disease (GVHD) in T-cell-depleted transplants [37]
Summary
Natural killer (NK) cells belong to innate lymphocytes that play an important role in the early phase of immune defense against microbial infections, and tumor growth and dissemination. With acute myeloid leukemia (AML) undergoing mismatched/ haploidentical hematopoietic stem cell transplantation (HSCT) This protocol of transplantation relied on the generation of alloreactive NK cells with a KIR repertoire unable to bind to host MHC class I molecules, and was associated with a 65% probability of disease-free survival, decreased incidence of relapse, and no increased incidence of graft versus host disease (GVHD) in T-cell-depleted transplants [37]. The initial findings outlined the importance of inhibitory KIRs on the outcome of HSCT, several later studies focused attention on the influence of activating KIRs. AML patients transplanted with HSC from donor with alloreactive NK cells carrying KIR2DS1 displayed a lower rate of leukemia relapse as compared to those carrying KIR3DS1 who had no effect on leukemic disease but showed a reduced risk of infection-related mortality [42]. Variation of the KIR gene family and the impact of KIR-ligand mismatch on the outcome of HSCT have been addressed
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