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Unconventional CD56dim/CD16neg NK cells in HSCT
hHSCT recipients. We found that the NK cell expression of CD94/NKG2A is remarkably increased after hHSCT. In particular, while only a fraction (median of 47,2 %±2,5 %) of uCD56dim NK cells from healthy donors is NKG2Apos, almost all uCD56dim NK cells expanded after hHSCT express this iNKR. The significant higher frequency of NKG2Apos/uCD56dim NK cells in the PB of recipients com- pared to their related healthy donors is detectable between the fourth and eleventh week following hHSCT (Figure 7C).
To understand if this high and transient expression of CD94/NKG2A on donor-derived uCD56dim NK cells recon- stituting the recipients could explain their defective cyto- toxicity, we performed masking experiments by blocking this iNKR in the presence of a tumor cell line expressing its putative ligand HLA-E (i.e., 721-221G cell line).35,36 Both cCD56bright and uCD56dim NK cells from healthy donors are able to efficiently degranulate, and the masking with an anti-CD94/NKG2A mAb increased the expression of CD107a only in cCD56bright, in line with their high consti- tutive expression of NKG2A. In contrast, both cCD56bright and uCD56dim NK cells purified from hHSCT after six
weeks from the transplant are not able to efficiently degranulate against 721-221G, and only the blocking of the CD94/NKG2A inhibitory checkpoint significantly increases the expression of CD107a of these NK cell sub- sets (Figure 7D).
Discussion
The recent development of TCRe-NMAC-PT/Cy hHSCT with RIC represented a revolution in the field of BMT for the cure of hematologic malignancies.1,2,37 The study herein characterizes the transient and early expan- sion of a functionally exhausted subset of donor-derived uCD56dim NK cells that is detectable at a high frequency from the second week after the transplant. uCD56dim NK cells are by far the largest NK cell population in the first weeks after hHSCT and are also characterized by a signif- icant higher expression of CD94/NKG2A compared to their counterparts in healthy donors. The increased sur- face levels of this iNKR early after hHSCT greatly impairs the cytotoxicity of uCD56dim NK cells, thus affecting those
AB
C
Figure 8. NK cell immune-reconstitution after haploidentical HSCT. (A) Natural killer (NK) cell ontogenesis (left): after the infusion of unmanipulated graft in non myeloablative haplo- hematopoietic stem cells transplant (hHSCT), the reconstitution of NK cells in recipients is completely donor-dependent and starts from CD34pos hematopoietic stem cells. Indeed, mature NK cells infused with the graft do not survive the PT infusion of cyclophosphamide.25 The first NK cell subsets to be detect- ed starting from the second week after hHSCT are the cCD56bright and uCD56dim NK cells, with the latter population being by far the largest one, expanded early in the first weeks after the transplant. cCD56bright and uCD56dim cells are not NK cell precursors and are able to exert a bi-directional differentiation following stimulation with IL-15, a pro-inflammatory cytokine present at high levels in the sera of lymphopenic recipients in the first weeks after allogeneic transplant.25,31 (B) Clinical impact (lower right): due to the high constitute expression of the inhibitory receptor NKG2A, uCD56dim NK cells are exhausted in their cytolic potential, and this impairment greatly affects: i) the clearance of residual malignant cells in the recipient that survived the conditioning regimens (i.e., decreased graft-versus-leukemia (GvL) effect), ii) the killing of recipient antigen presenting cells (APCs) presenting host antigens to donor T cells (i.e., increase in the onset of graft-versus-host disease [GvHD]), and iii) the elimination of recipient immune T cells that survived the conditioning regimens (i.e., decrease in engraftment).7 (C) Therapeutic insights (upper right): the blocking of the NKG2A inhibitory checkpoint unleashes donor-derived NK cell cytotoxicity and increases their alloreactive potential. Hence, the PT infusion of the humanized anti-NKG2A monoclonal antibody (i.e., Monalizumab) represents a potential novel therapeutic approach to improve the clinical outcome of hHSCT.
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