Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma

Abstract

Hematopoietic stem cell transplantation (HSCT) is a frequent therapeutic approach to restore hematopoiesis in patients with hematologic diseases. Patients receive a hematopoietic stem cell (HSC)-enriched donor cell infusion also containing immune cells, which may have a beneficial effect by eliminating residual neoplastic cells. However, the effect that donor innate immune cells may have on the donor HSCs has not been deeply explored. Here, we evaluate the influence of donor natural killer (NK) cells on HSC fate, concluded that NK cells negatively affect HSC frequency and function, and identified interferon-gamma (IFNg) as a potential mediator. Interestingly, improved HSC fitness was achieved by NK cell depletion from murine and human donor infusions or by blocking IFNg activity. Thus, our data suggest that suppression of inflammatory signals generated by donor innate immune cells can enhance engraftment and hematopoietic reconstitution during HSCT, which is particularly critical when limited HSC numbers are available and the risk of engraftment failure is high.

NK cell content does not seem to influence engraftment in ex vivo T cell depleted haploidentical stem cell transplantation

“…We read with great interest the manuscript by Lobo de Figueiredo-Pontes and colleagues ( Lobo de Figueiredo-Pontes et al., 2021 ) on the potential clinical usefulness of NK cell-derived IFNγ inhibition to favor engraftment in allogeneic hematopoietic stem cell transplantation (HSCT). Indeed, the role of IFNγ in regulating hematopoiesis during acute or chronic inflammation through modulation of transcription factor expression and perturbation of cytokine signaling is well characterized ( Merli et al., 2021 ).…”

Response to NK cell content does not seem to influence engraftment in ex vivo T cell depleted haploidentical stem cell transplantation

“…In our recent publication in Stem Cell Reports ( Lobo de Figueiredo-Pontes et al., 2021 ), we assessed the role of NK cells on hematopoietic stem cell (HSC) fate during HSC transplantation and concluded that NK cells, possibly via secretion of cytokines (and in particular IFNγ), negatively affect HSC frequency and function. In their letter in this issue of Stem Cell Reports , Merli and colleagues report carrying out an interesting attempt to translate our observations to clinics ( Merli et al., 2022 ).…”

“…However, we do not favor NK cell removal from any graft, but rather, “we would like to propose that NK cell depletion may actually favor HSC donor engraftment in the setting of allogeneic transplantation for non-neoplastic diseases in selected patients. Such cases would include, for instance, but are not limited to, patients with idiopathic severe aplastic anemia or sickle cell anemia” (see our original manuscript by Lobo de Figueiredo-Pontes et al., 2021 ). Therefore, we would not expect that NK cell depletion would exhibit beneficial effects in a mixed and random cohort of transplanted patients.…”

Stem Cell Therapy and Innate Lymphoid Cells

“…A recent study suggested that NK cells negatively regulate the number and function of transplanted HSCs in both humans and mice, and it works in a dose-dependent manner which is mediated by IFN- γ . In the same study, it was demonstrated that this negative effect of NK cells was restored by depletion of NK cells or by blocking the IFN- γ signaling [ 2 , 25 ]. Zhu et al reported that deletion of cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) in human iPSC-derived NK cells promoted the expansion of NK cells and increased the cytotoxic activity against multiple tumor cell lines when maintained at low concentrations of cytokine interleukin-15 (IL-15) ( Figure 2 ) [ 26 ].…”